黄酮和黄酮醇对两株人食管癌细胞的抑制作用
|
摘要
大量证据表明,摄入植物性食物特别是蔬菜和水果,能够降低各种癌症的发病风险。植物性食物含有的多种生物活性物质(植物化学成分),是其发挥抗癌活性的重要成分。类黄酮化合物是广泛存在于食用性植物中的多酚类化合物,根据化学结构可分为黄酮醇化合物、黄酮化合物、黄烷酮化合物、黄烷醇化合物、花色苷化合物、异黄酮化合物、二氢黄酮醇化合物以及查耳酮化合物等。许多体内外研究、流行病学调查以及某些临床应用结果表明,类黄酮化合物对于癌症的预防和治疗具有积极作用。但是,类黄酮化合物发挥抗癌活性的内在分子机制,仍有待进一步研究。
世界范围内,食管癌在恶性肿瘤中排位第九,约占胃肠癌发病总数的7%,是所有肿瘤中最具致死性的癌症之一。食管癌主要包括两种类型,食管鳞癌(占食管癌总数的90%以上)和食管腺癌(占食管癌总数的10%以下)。大量流行病学研究结果表明,食管癌的发生不仅与饮酒、吸烟、致癌物的摄入以及热损伤直接相关,而且与食物中蔬菜和水果的摄入不足存在密切关系。膳食类黄酮化合物作为蔬菜和水果中的生物活性成分,很可能会为食管癌的预防带来新的希望。
本课题研究化学结构相似的黄酮和黄酮醇化合物,对人食管鳞癌细胞系KYSE-510细胞和人食管腺癌细胞系OE33细胞的抑制作用。MTT分析结果表明,黄酮化合物(木犀草素、芹菜素和白杨素)和黄酮醇化合物(槲皮素、山奈酚和杨梅素),均能以剂量-效应和时间-效应依赖方式,抑制KYSE-510和OE33细胞增殖。它们对KYSE-510和OE33细胞增殖的抑制活性强弱顺序分别为:木犀草素＞槲皮素＞白杨素＞山奈酚＞芹菜素＞杨梅素和槲皮素＞木犀草素＞白杨素＞山奈酚＞芹菜素＞杨梅素。上述结果表明,这些化合物分子中的3'-OH可能有助于黄酮和黄酮醇化合物对KYSE-510和OE33细胞的增殖抑制活性,而分子中的4'-OH和3-OH可能降低化合物抗癌活性的发挥。同时,黄酮化合物和黄酮醇化合物对KYSE-510和OE33细胞的增殖抑制活性,不依赖于分子中的-OH总数。
流式细胞仪检测结果显示,黄酮化合物和黄酮醇化合物能够诱导KYSE-510和OE33细胞的周期循环停滞于G_2/M期,并且化合物对KYSE-510和OE33细胞G_2/M周期停滞的诱导活性强弱顺序与MTT检测结果一致,表明黄酮化合物和黄酮醇化合物可能通过诱导细胞周期停滞,抑制两株食管癌细胞增殖。另外,DNA片段化检测和吖啶橙荧光染色结果显示,KYSE-510和OE33细胞经黄酮化合物和黄酮醇化合物作用后,两株细胞均出现了细胞凋亡的典型特征,表明两类化合物能够诱导KYSE-510和OE33细胞发生细胞凋亡。采用FITC-annexin V和PI双荧光标记,通过流式细胞仪定量比较两类化合物对KYSE-510和OE33细胞的凋亡诱导活性,相应实验数据显示,黄酮化合物和黄酮醇化合物对两株食管癌细胞的凋亡诱导活性强弱顺序,与其G_2/M细胞周期停滞的诱导活性强弱顺序以及细胞增殖抑制活性强弱顺序完全一致,表明黄酮化合物和黄酮醇化合物可通过诱导细胞周期停滞和细胞凋亡,实现对两株人食管癌细胞增殖的有效抑制。
为探明黄酮化合物和黄酮醇化合物抑制KYSE-510和OE33细胞的分子机制,采用基因芯片技术检测两株食管癌细胞中基因的表达改变。结果表明,KYSE-510细胞经木犀草素作用后,表达改变倍数大于1.5的基因共有75个,其中与细胞增殖、细胞周期循环和细胞凋亡相关的上调表达基因有3个(p21~(waf1)、PIG3和egr-1),下调表达基因有5个(cyclin B1、PSCA、vav3、WISP2和ear-1);OE33细胞经槲皮素作用后,表达改变倍数大于1.5的基因共有52个,其中与细胞增殖、细胞周期循环和细胞凋亡相关的上调表达基因有4个(PIG3、GADD45β、p18和14-3-3s),下调表达基因有3个(cyclin B1、PSCA和FBP1)。
为验证两株食管癌细胞中基因表达的芯片检测结果,采用荧光定量RT-PCR对上述KYSE-510细胞中的8个基因以及OE33细胞中的7个基因的mRNA表达水平进行分析,并比较6种黄酮、黄酮醇化合物对各基因表达的调控能力。各基因表达的荧光定量RT-PCR分析结果,与相应基因芯片的分析结果相符,表明基因芯片分析结果较为准确可靠。荧光定量RT-PCR分析结果还显示,在KYSE-510细胞中,黄酮化合物和黄酮醇化合物对3个基因(p21~(waf1)、PIG3和cyclin B1)表达的调控活性强弱,对应于其G_2/M细胞周期停滞和细胞凋亡的诱导活性强弱;在OE33细胞中,黄酮化合物和黄酮醇化合物对4个基因(PIG3、GADD45B、14-3-3s和cyclin B1)表达的调控活性强弱,对应于其G_2/M细胞周期停滞和细胞凋亡的诱导活性强弱。上述结果说明,KYSE-510细胞中的p21~(waf1)、PIG3和cyclin B1以及OE33细胞中的PIG3、GADD45B、14-3-3s和cyclin B1为介导黄酮和黄酮醇化合物诱导细胞周期停滞和细胞凋亡的目标基因。
为确定上述目标基因的mRNA表达水平改变是否最终导致相应蛋白的表达水平变化,采用Western-blot检测了上述目标基因的蛋白表达水平。检测结果表明,黄酮化合物和黄酮醇化合物通过增加p21~(waf1)的蛋白表达并抑制cyclin B1的蛋白表达,诱导KYSE-510细胞发生G_2/M周期停滞;通过增加GADD45B和14-3-3s的蛋白表达并抑制cyclin B1的蛋白表达,诱导OE33细胞发生G_2/M周期停滞。同时,黄酮化合物和黄酮醇化合物通过增加PIG3的蛋白表达,提高活体caspase-9和caspase-3的蛋白水平,诱导KYSE-510和OE33细胞发生非p53依赖的线粒体介导的细胞凋亡。Western-blot进一步分析表明,黄酮和黄酮醇化合物可能通过增加p63和p73蛋白翻译或蛋白稳定性,调控p21~(waf1)、GADD45β、14-3-3s、cyclin B1和PIG3等基因的表达。
Evidence has been accumulated indicating that dietary intake of plant-based diets,in particular those rich in vegetables and fruits,can reduce the risk of human cancers.Plant-derived foods generally are good sources of many bioactive compounds(phytochemicals) which are contributed to anticancer activity of these foods.Flavonoids are a group of polyphenols and are ubiquitously found in food plants,and are categorized,according to chemical structure,into flavones,flavonols, isoflavones,flavanols,flavanones,flavanonols,isoflavones and chalcones.Compelling data from in vitro and in vivo laboratory studies,epidemiological investigations,and human clinical trials indicate that flavonoids have important effects on cancer chemoprevention and therapy.However, the molecular basis of the effect of flavonoids on cancer remains to be elucidated.
Cancer of the esophagus has been reported as the ninth most common malignancy in the world. It also constitutes 7%of all gastrointestinal cancers and is one of the most lethal of all cancers. There are two main forms of esophageal cancer,each with distinct etiological and pathological characteristics:squamous cell carcinoma(＞90%of esophageal malignancies) and adenocareinoma (＜10%of esophageal malignancies).There is considerable epidemiological evidence suggesting that diets deficient in vegetables and fruits are important in the pathogenesis of esophageal cancer, apart from alcohol,tobacco,intake of carcinogens and thermal injuries.As a large number of bioactive ingredients in vegetables and fruits,dietary flavonoids may bring new hope to the prevention of esophageal cancer.
In this study,inhibitory effects of structurally related flavones and flavonols on a human esophageal squamous cell carcinoma cell line(KYSE-510) and a human oesophageal adenocarcinoma cell line(OE33) were studied.The results of MTT assay showed that flavones (luteolin,apigenin and chrysin) and flavonols(quercetin,kaempferol and myricetin) were all able to inhibit proliferation of KYSE-510 and OE33 cells in a dose- and time-dependent manner.The potency of these flavonoids on inhibition of KYSE-510 and OE33 cells was in the order of luteolin＞quercetin＞chrysin＞kaempferol＞apigenin＞myricetin and quercetin＞luteolin＞chrysin＞kaempferol＞apigenin＞myricetin,respectively.These results suggested that the inhibitory effect of flavones and flavonols on proliferation of KYSE-510 and OE33 cells might be dependent on the presence of 3'-hydroxyl group and/or the absence of 4'-hydroxyl group and 3-hydroxyl group in these compounds,but independent on the number of hydroxyl groups.
Flow cytometric analysis indicated that flavones and flavonols were able to induce cell cycle arrest in G_2/M phase in KYSE-510 and OE33.In agreement with the results of MTT assay,similar potency of these flavonoids on induction of G_2/M arrest in KYSE-510 and OE33 cells was also observed,respectively.It was suggested that inhibitory effects of flavones and flavonols might be mediated by G_2/M cell cycle arrest.Moreover,KYSE-510 and OE-33 cells treated with flavones and flavonols displayed typical characteristics of apoptosis by DNA fragmentation and acridine orange staining methods.The apoptosis induced by these flavonoids was quantified by flow cytometry after labeling the cells with FITC-annexin V/PI.The data showed that potency of these flavonoids on induction of apoptosis was also similar to that observed on growth inhibition and G_2/M cell cycle arrest.It was suggested that flavones and flavonols inhibited proliferation of KYSE-510 and OE33 ceils by causing cell cycle arrest and inducing apoptosis.
To gain insight into the molecular mechanisms underlying inhibitory effects of flavones and flavonols on KYSE-510 and OE33 cells,the expression of genes was assessed by gene chip. Seventy-five genes showed＞1.5-fold change in KYSE-510 cells treated with luteolin.Among these genes,three genes(p21~(wafl),PIG3 and egr-1) were up-regulated and five genes(cyclin B1, PSCA,vav3,WISP2 and ear-1) were down-regulated,which are related to cell proliferation,cell cycle progression and apoptosis.Fifty-two genes showed＞1.5-fold change in OE33 cells treated with quercetin.Among these genes,four genes(PIG3,GADD45β,p18 and 14-3-3s) were up-regulated and three genes(cyclin B1,PSCA and FBP1) were down-regulated.
To verify the alterations of gene expression in two esophageal cancer cells at the mRNA level, which appeared in the microarray,we conducted real-time RT-PCR analysis for eight genes in KYSE-510 and seven genes in OE33 cells.Moreover,comparative effects of all six flavonoids on the regulation of these gene expressions were also assayed by real-time RT-PCR.The results of real-time RT-PCR analysis for these genes were in direct agreement with the microarray data.In KYSE-510 cells,alterations in expression levels of three genes(p21~(wafl),PIG3 and cyclin B1) were corresponding to the potency of flavones and flavonols on induction of cell cycle arrest and apoptosis.In OE33 cells,alterations in expression levels of four genes(PIG3,GADD45β,14-3-3s and cyclin B1) were corresponding to the potency of flavones and flavonols on induction of cell cycle arrest and apoptosis.It was suggested that p21~(wafl),PIG3 and cyclin B1 in KYSE-510 cells and PIG3,GADD45β,14-3-3s and cyclin B1 in OE33 cells were the target genes which mediated cell cycle arrest and apoptosis induced by flavones and flavonols.
To verify whether the alternations in expression of these target genes at the mRNA level ultimately result in the alternations at the protein level,we conducted a series of Western-blot analyses for them.It was found that flavones and flavonols caused G_2/M arrest through up-regulation of p21~(wafl) and down-regulation of cyclin B1 at the protein level in KYSE-510 cells, and caused G_2/M arrest through up-regulation of GADD45βand 14-3-3s and down-regulation of cyclin B1 at the protein level in OE33 cells.Flavones and flavonols induced p53-independent mitochondrial-mediated apoptosis through up-regulation of PIG3 and cleavage of caspase-9 and caspase-3 at the protein level in KYSE-510 cells and OE33 cells.The results of Western-blot analysis further showed that increases of p63 and p73 protein translation or stability might be responsible for the regulation of p21~(wafl),GADD45g,14-3-3s,cyclin B1 and PIG3.
世界范围内,食管癌在恶性肿瘤中排位第九,约占胃肠癌发病总数的7%,是所有肿瘤中最具致死性的癌症之一。食管癌主要包括两种类型,食管鳞癌(占食管癌总数的90%以上)和食管腺癌(占食管癌总数的10%以下)。大量流行病学研究结果表明,食管癌的发生不仅与饮酒、吸烟、致癌物的摄入以及热损伤直接相关,而且与食物中蔬菜和水果的摄入不足存在密切关系。膳食类黄酮化合物作为蔬菜和水果中的生物活性成分,很可能会为食管癌的预防带来新的希望。
本课题研究化学结构相似的黄酮和黄酮醇化合物,对人食管鳞癌细胞系KYSE-510细胞和人食管腺癌细胞系OE33细胞的抑制作用。MTT分析结果表明,黄酮化合物(木犀草素、芹菜素和白杨素)和黄酮醇化合物(槲皮素、山奈酚和杨梅素),均能以剂量-效应和时间-效应依赖方式,抑制KYSE-510和OE33细胞增殖。它们对KYSE-510和OE33细胞增殖的抑制活性强弱顺序分别为:木犀草素＞槲皮素＞白杨素＞山奈酚＞芹菜素＞杨梅素和槲皮素＞木犀草素＞白杨素＞山奈酚＞芹菜素＞杨梅素。上述结果表明,这些化合物分子中的3'-OH可能有助于黄酮和黄酮醇化合物对KYSE-510和OE33细胞的增殖抑制活性,而分子中的4'-OH和3-OH可能降低化合物抗癌活性的发挥。同时,黄酮化合物和黄酮醇化合物对KYSE-510和OE33细胞的增殖抑制活性,不依赖于分子中的-OH总数。
流式细胞仪检测结果显示,黄酮化合物和黄酮醇化合物能够诱导KYSE-510和OE33细胞的周期循环停滞于G_2/M期,并且化合物对KYSE-510和OE33细胞G_2/M周期停滞的诱导活性强弱顺序与MTT检测结果一致,表明黄酮化合物和黄酮醇化合物可能通过诱导细胞周期停滞,抑制两株食管癌细胞增殖。另外,DNA片段化检测和吖啶橙荧光染色结果显示,KYSE-510和OE33细胞经黄酮化合物和黄酮醇化合物作用后,两株细胞均出现了细胞凋亡的典型特征,表明两类化合物能够诱导KYSE-510和OE33细胞发生细胞凋亡。采用FITC-annexin V和PI双荧光标记,通过流式细胞仪定量比较两类化合物对KYSE-510和OE33细胞的凋亡诱导活性,相应实验数据显示,黄酮化合物和黄酮醇化合物对两株食管癌细胞的凋亡诱导活性强弱顺序,与其G_2/M细胞周期停滞的诱导活性强弱顺序以及细胞增殖抑制活性强弱顺序完全一致,表明黄酮化合物和黄酮醇化合物可通过诱导细胞周期停滞和细胞凋亡,实现对两株人食管癌细胞增殖的有效抑制。
为探明黄酮化合物和黄酮醇化合物抑制KYSE-510和OE33细胞的分子机制,采用基因芯片技术检测两株食管癌细胞中基因的表达改变。结果表明,KYSE-510细胞经木犀草素作用后,表达改变倍数大于1.5的基因共有75个,其中与细胞增殖、细胞周期循环和细胞凋亡相关的上调表达基因有3个(p21~(waf1)、PIG3和egr-1),下调表达基因有5个(cyclin B1、PSCA、vav3、WISP2和ear-1);OE33细胞经槲皮素作用后,表达改变倍数大于1.5的基因共有52个,其中与细胞增殖、细胞周期循环和细胞凋亡相关的上调表达基因有4个(PIG3、GADD45β、p18和14-3-3s),下调表达基因有3个(cyclin B1、PSCA和FBP1)。
为验证两株食管癌细胞中基因表达的芯片检测结果,采用荧光定量RT-PCR对上述KYSE-510细胞中的8个基因以及OE33细胞中的7个基因的mRNA表达水平进行分析,并比较6种黄酮、黄酮醇化合物对各基因表达的调控能力。各基因表达的荧光定量RT-PCR分析结果,与相应基因芯片的分析结果相符,表明基因芯片分析结果较为准确可靠。荧光定量RT-PCR分析结果还显示,在KYSE-510细胞中,黄酮化合物和黄酮醇化合物对3个基因(p21~(waf1)、PIG3和cyclin B1)表达的调控活性强弱,对应于其G_2/M细胞周期停滞和细胞凋亡的诱导活性强弱;在OE33细胞中,黄酮化合物和黄酮醇化合物对4个基因(PIG3、GADD45B、14-3-3s和cyclin B1)表达的调控活性强弱,对应于其G_2/M细胞周期停滞和细胞凋亡的诱导活性强弱。上述结果说明,KYSE-510细胞中的p21~(waf1)、PIG3和cyclin B1以及OE33细胞中的PIG3、GADD45B、14-3-3s和cyclin B1为介导黄酮和黄酮醇化合物诱导细胞周期停滞和细胞凋亡的目标基因。
为确定上述目标基因的mRNA表达水平改变是否最终导致相应蛋白的表达水平变化,采用Western-blot检测了上述目标基因的蛋白表达水平。检测结果表明,黄酮化合物和黄酮醇化合物通过增加p21~(waf1)的蛋白表达并抑制cyclin B1的蛋白表达,诱导KYSE-510细胞发生G_2/M周期停滞;通过增加GADD45B和14-3-3s的蛋白表达并抑制cyclin B1的蛋白表达,诱导OE33细胞发生G_2/M周期停滞。同时,黄酮化合物和黄酮醇化合物通过增加PIG3的蛋白表达,提高活体caspase-9和caspase-3的蛋白水平,诱导KYSE-510和OE33细胞发生非p53依赖的线粒体介导的细胞凋亡。Western-blot进一步分析表明,黄酮和黄酮醇化合物可能通过增加p63和p73蛋白翻译或蛋白稳定性,调控p21~(waf1)、GADD45β、14-3-3s、cyclin B1和PIG3等基因的表达。
Evidence has been accumulated indicating that dietary intake of plant-based diets,in particular those rich in vegetables and fruits,can reduce the risk of human cancers.Plant-derived foods generally are good sources of many bioactive compounds(phytochemicals) which are contributed to anticancer activity of these foods.Flavonoids are a group of polyphenols and are ubiquitously found in food plants,and are categorized,according to chemical structure,into flavones,flavonols, isoflavones,flavanols,flavanones,flavanonols,isoflavones and chalcones.Compelling data from in vitro and in vivo laboratory studies,epidemiological investigations,and human clinical trials indicate that flavonoids have important effects on cancer chemoprevention and therapy.However, the molecular basis of the effect of flavonoids on cancer remains to be elucidated.
Cancer of the esophagus has been reported as the ninth most common malignancy in the world. It also constitutes 7%of all gastrointestinal cancers and is one of the most lethal of all cancers. There are two main forms of esophageal cancer,each with distinct etiological and pathological characteristics:squamous cell carcinoma(＞90%of esophageal malignancies) and adenocareinoma (＜10%of esophageal malignancies).There is considerable epidemiological evidence suggesting that diets deficient in vegetables and fruits are important in the pathogenesis of esophageal cancer, apart from alcohol,tobacco,intake of carcinogens and thermal injuries.As a large number of bioactive ingredients in vegetables and fruits,dietary flavonoids may bring new hope to the prevention of esophageal cancer.
In this study,inhibitory effects of structurally related flavones and flavonols on a human esophageal squamous cell carcinoma cell line(KYSE-510) and a human oesophageal adenocarcinoma cell line(OE33) were studied.The results of MTT assay showed that flavones (luteolin,apigenin and chrysin) and flavonols(quercetin,kaempferol and myricetin) were all able to inhibit proliferation of KYSE-510 and OE33 cells in a dose- and time-dependent manner.The potency of these flavonoids on inhibition of KYSE-510 and OE33 cells was in the order of luteolin＞quercetin＞chrysin＞kaempferol＞apigenin＞myricetin and quercetin＞luteolin＞chrysin＞kaempferol＞apigenin＞myricetin,respectively.These results suggested that the inhibitory effect of flavones and flavonols on proliferation of KYSE-510 and OE33 cells might be dependent on the presence of 3'-hydroxyl group and/or the absence of 4'-hydroxyl group and 3-hydroxyl group in these compounds,but independent on the number of hydroxyl groups.
Flow cytometric analysis indicated that flavones and flavonols were able to induce cell cycle arrest in G_2/M phase in KYSE-510 and OE33.In agreement with the results of MTT assay,similar potency of these flavonoids on induction of G_2/M arrest in KYSE-510 and OE33 cells was also observed,respectively.It was suggested that inhibitory effects of flavones and flavonols might be mediated by G_2/M cell cycle arrest.Moreover,KYSE-510 and OE-33 cells treated with flavones and flavonols displayed typical characteristics of apoptosis by DNA fragmentation and acridine orange staining methods.The apoptosis induced by these flavonoids was quantified by flow cytometry after labeling the cells with FITC-annexin V/PI.The data showed that potency of these flavonoids on induction of apoptosis was also similar to that observed on growth inhibition and G_2/M cell cycle arrest.It was suggested that flavones and flavonols inhibited proliferation of KYSE-510 and OE33 ceils by causing cell cycle arrest and inducing apoptosis.
To gain insight into the molecular mechanisms underlying inhibitory effects of flavones and flavonols on KYSE-510 and OE33 cells,the expression of genes was assessed by gene chip. Seventy-five genes showed＞1.5-fold change in KYSE-510 cells treated with luteolin.Among these genes,three genes(p21~(wafl),PIG3 and egr-1) were up-regulated and five genes(cyclin B1, PSCA,vav3,WISP2 and ear-1) were down-regulated,which are related to cell proliferation,cell cycle progression and apoptosis.Fifty-two genes showed＞1.5-fold change in OE33 cells treated with quercetin.Among these genes,four genes(PIG3,GADD45β,p18 and 14-3-3s) were up-regulated and three genes(cyclin B1,PSCA and FBP1) were down-regulated.
To verify the alterations of gene expression in two esophageal cancer cells at the mRNA level, which appeared in the microarray,we conducted real-time RT-PCR analysis for eight genes in KYSE-510 and seven genes in OE33 cells.Moreover,comparative effects of all six flavonoids on the regulation of these gene expressions were also assayed by real-time RT-PCR.The results of real-time RT-PCR analysis for these genes were in direct agreement with the microarray data.In KYSE-510 cells,alterations in expression levels of three genes(p21~(wafl),PIG3 and cyclin B1) were corresponding to the potency of flavones and flavonols on induction of cell cycle arrest and apoptosis.In OE33 cells,alterations in expression levels of four genes(PIG3,GADD45β,14-3-3s and cyclin B1) were corresponding to the potency of flavones and flavonols on induction of cell cycle arrest and apoptosis.It was suggested that p21~(wafl),PIG3 and cyclin B1 in KYSE-510 cells and PIG3,GADD45β,14-3-3s and cyclin B1 in OE33 cells were the target genes which mediated cell cycle arrest and apoptosis induced by flavones and flavonols.
To verify whether the alternations in expression of these target genes at the mRNA level ultimately result in the alternations at the protein level,we conducted a series of Western-blot analyses for them.It was found that flavones and flavonols caused G_2/M arrest through up-regulation of p21~(wafl) and down-regulation of cyclin B1 at the protein level in KYSE-510 cells, and caused G_2/M arrest through up-regulation of GADD45βand 14-3-3s and down-regulation of cyclin B1 at the protein level in OE33 cells.Flavones and flavonols induced p53-independent mitochondrial-mediated apoptosis through up-regulation of PIG3 and cleavage of caspase-9 and caspase-3 at the protein level in KYSE-510 cells and OE33 cells.The results of Western-blot analysis further showed that increases of p63 and p73 protein translation or stability might be responsible for the regulation of p21~(wafl),GADD45g,14-3-3s,cyclin B1 and PIG3.
引文
曹良启,王晓黎,刘德育.2004.黄酮类化合物诱导肿瘤细胞凋亡的研究进展.中药材.27(10):785-788.
常徽,糜漫天.2006.植物黄酮抗肿瘤研究进展.国外医学卫生学分册.33(5):296-300.
陈业高.2004.植物化学成分.第一版.化学工业出版社.172-217.
高昕,王喜军.2005.黄酮类化合物抗肿瘤作用研究进展.中医药信息.22(5):33-34.
黄华艺,查锡良.2002.黄酮类化合物抗肿瘤作用研究进展.中国新药与临床杂志.21(7):428-433.
李荣,李俊.2005.黄酮类化合物药理活性及其构效关系研究进展.安徽医药.9(7):481-483.
刘舒,韩静,王绿娅.2004.黄酮、异黄酮药物抑制肿瘤细胞增殖作用的最新进展.中国药学杂志.39(1):4-7.
裴利宽,郭宝林.2006.黄酮类化合物吸收和代谢研究进展.中国药学杂志.41(8):568-572.
施明.2001.类黄酮抗肿瘤作用的研究进展.国外医学卫生学分册.28(2):96-99.
汤立建,赵良才,李庆林等.2007.黄芩黄酮类成分抗肿瘤作用及机制研究进展.中国中药杂志.32(1):21-24.
张汆,阚建全,陈宗道.2003.生物类黄酮抗癌作用研究进展.中国野生植物资源.22(4):8-11.
张玉霞,喻伦银,刘铭球.2001.细胞周期调控研究进展.国外医学遗传学分册.24(5):262-266.
钟晓刚,吴凯南.2001.槲皮素逆转肿瘤多药耐药的研究进展.国外医学肿瘤学分册.28(3):202-204.
朱会平.2006.黄酮类化合物促进癌细胞凋亡的分子机理研究进展.生物技术通讯.17(3):455-456.
Agarwal C.,Singh R.P.,Dhanalakshmi S.,et al.2003.Silibinin upregulates the expression of cyclin-dependent kinase inhibitors and causes cell cycle arrest and apoptosis in human colon carcinoma HT-29 cells.Oncogene.22(51):8271-8282.
Agnero M.F.,Facchinetti M.M.,Sheleg Z.,et al.2005.Phenoxodiol,a novel isoflavone,induces G1 arrest by specific loss in cyclin-dependent kinase 2 activity by p53-independent induction of p21WAF1/CIP1.Cancer Res.65(8):3364-3373.
Ahn Y.M.,Vogeti L.,Liu C.Jing.,et al.2007.Design,synthesis,and antiproliferative and CDK2-cyclin:A inhibitory activity of novel flavopiridol analogues.Bioorg.Med.Chem.15(2):702-713.
Aligiannis N.,Mitaku S.,Mitrocotsa D.,et al.2001.Flavonoids as cycline-dependent kinase inhibitors:inhibition of cdc 25 phosphatase activity by flavonoids belonging to the quercetin and kaempferol series.Planta.Med.67(5):468-470.
American Dietetic Association 1995.Position of the American Dietetic Association:phytochemicals and functional foods.J.Am.Diet Assoc.95(4):493-496.
Arts I.C.,Sesinka L.,Faassen-Peters M.,et al.2004.The type of sugar moiety is a major determinant of the small intestinal uptake and subsequent biliary excretion of dietary quercetin glycosides. Br. J. Nutr. 91(6): 841-847.
Atkinson C, Berman S., Humbert O., et al. 2004. In vitro incubation of human feces with daidzein and antibiotics suggests interindividual differences in the bacteria responsible for equol production. J. Nutr. 134(3): 596-599.
Bagli E., Stefaniotou M., Morbidelli L., et al. 2004. Luteolin inhibits vascular endothelial growth factor-induced angiogenesis; inhibition of endothelial cell survival and proliferation by targeting Phosphatidylinositol 3' -kinase activity. Cancer Research. 64(21): 7936-7946.
Beecher G R. 2003. Overview of dietary flavonoids: nomenclature, occurrence and intake. J. Nutr. 133(10): 3248S-3254S.
Bestwick C.S., Milne L., Duthie S.J. 2007. Kaempferol induced inhibition of HL-60 cell growth results from a heterogeneous response, dominated by cell cycle alterations. Chem. Biol. Interact. 170(2): 76-85.
Bingham S., Riboli E. 2004. Diet and cancer-the European prospective investigation into cancer and nutrition. Nature Reviews. 4(3): 206-215.
Birt D.F., Hendrich S., and Wang W. 2001. Dietary agents in cancer prevention: flavonoids and isoflavonoids. Pharmacol Ther. 90(2-3): 157-177.
Birt D.F., Mitchell D., Gold B., et al. 1997. Inhibition of ultraviolet light induced skin carcinogenesis in SKH-1 mice by apigenin, a plant flavonoid. Anticancer Res. 17(1A): 85-91.
Bloch A. S. 2000. Phytochemicals and functional foods for cancer risk reduction. Top Clin Nutr. 15(2): 24-28.
Block G., Patterson B., Subar A. 1992. Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Nutr. Cancer. 18(1): 1-29.
Bokkenheuser V.D., Shackleton C.H.L., Winter J. 1987. Hydrolysis of dietary flavonoid glycosides by strains of intestinal Bacteroides from humans. Biochem J. 248(3): 953-956.
Bosetti C, Rossi Marta., McLaughlin J.K., et al. 2007. Flavonoids and the risk of renal cell carcinoma. Cancer Epidemiol Biomarkers Prev. 16(1): 98-101.
Bosetti C, Spertini L., Parpinel M., et al. 2005. Flavonoids and breast cancer risk in Italy. Cancer Epidemiol Biomarkers Prev. 14(4): 805-808.
Boulaire J, Fotedar A, Fotedar R. 2000. The functions of the cdk-cyclin kinase inhibitor p21WAF1. Pathol. Biol. (Paris). 48(3): 190-202.
Bowey E., Adlercreutz H., Rowland I. 2003. Metabolismof isoflavonesand lignans by the gut microflora: a study in germ-free and human flora associated rats. Food Chem. Toxicol. 41(5): 631-636.
Bracke M.E., Vyncke B.M., Van Laebeke N.A., et al. 1989. The flavonoid tangeretin inhibits invasion of M04 mouse cells into embryonic chick heart in vitro. Clin. Exp. Metastasis. 7(3): 283-300.
Braune A., Gutschow M., Engst W., et al. 2001. Degradation of quercetin and luteolin by eubacterium ramulus. Appl. Environ. Microbiol. 67(12): 5558-5567.
Brown J.M., Wouters B.G. 1999. Apoptosis, p53, and tumor cell sensitivity to anticancer agents. Cancer Res. 59(7): 1391-1399.
Brusselmans K., Vrolix R., Verhoeven G., et al. 2005. Induction of cancer cell apoptosis by flavonoids is associated with their ability to inhibit fatty acid synthase activity. J. Biol. Chem. 280(7): 5636-5645.
Casagrande F., Darbon J.M. 2001. Effects of structurally related flavonoids on cell cycle progression of human melanoma cells: regulation of cyclin-dependent kinases CDK2 and CDK1. Biochem. Pharmacol. 61(10): 1205-1215.
Cayrol C, Knibiehler M., Ducommun B. 1998. p21 binding to PCNA causes G1 and G2 cell cycle arrest in p53-deficient cells. Oncogene. 16(3): 311-320.
Chan F. L., Choi H.L., Chen Z.Y., et al. 2000. Induction of apoptosis in prostate cancer cell lines by a favonoid, baicalin. Cancer Lett. 160(2): 219-228.
Chan T.A., Hermeking H., Lengauer C, et al. 1999. 14-3-3 Sigma is required to prevent mitotic catastrophe after DNA damage. Nature. 401(6753): 616-620.
Chan T.S., Galati G, Pannala A.S., et al. 2003. Simultaneous detection of the antioxidant and pro-oxidant activity of dietary polyphenolics in a peroxidase system. Free Radic. Res. 37(7): 787-794.
Chang J., Hsu Y, Kuo P., et al. 2005. Increase of Bax/Bcl-XL ratio and arrest of cell cycle by luteolin in immortalized human hepatoma cell line. Life Sciences. 76(16): 1883-1893.
Chang K.L., Kung M.L., Chow N.H., et al. 2004. Genistein arrests hepatoma cells at G2/M phase: involvement of ATM activation and upregulation of p21wafl/cipl and Weel. Biochem. Pharmacol. 67(4): 717-26.
Chen K.H., Weng M.S., Lin J.K. 2007. Tangeretin suppresses IL-1B-induced cyclooxygenase (COX)-2 expression through inhibition of p38 MAPK, JNK, and AKT activation in human lung carcinoma cells. Biochem. Pharmacology. 73(2): 215-227.
Chiang L.C., Ng L.T., Lin I.C., et al. 2006. Anti-proliferative effect of apigenin and its apoptotic induction in human Hep G2 cells. Cancer Letters. 237(2): 207-214.
Cohen G.M. 1997. Caspases: the executioners of apoptosis. Biochem. J. 326( Pt 1): 1-16.
Compte, G., Daskiewicz, J.B., Bayet, C., et al. 2001. C-Isoprenylation of flavonoids enhances binding affinity toward P-glycoprotein and modulation of cancer cell chemoresistance. Med. Chem. 44(5): 763-768.
Conseil, G., Baubichon-Cortay, H., Dayan, G., et al. 1998. Flavonoids: a class of modulators with bifunctional interactions at vicinal ATP- and steroid-binding sites on mouse P-glycoprotein. Proc. Natl. Acad. Sci. U. S. A. 95(17): 9831-9836.
Cooke D., Steward W.P., Gescher A.J., et al. 2005. Anthocyans from fruits and vegetables-Does bright colour signal cancer chemopreventive activity? Eur. J. Cancer. 41(13): 1931-1940.
Cummings J. H., Bingham S. A. 1998. Diet and the prevention of cancer. B.M.J. 317(7173): 1636-1640.
Darragh J., Hunter M., Pohler E., et al. 2006. The calcium-binding domain of the stress protein SEP53 is required for survival in response to deoxycholic acid-mediated injury. FEBS J. 273(9): 1930-1947.
Das S., Rosazza J.P. 2006. Microbial and enzymatic transformations of flavonoids. J. Nat. Prod. 69(3): 499-508.
Davies T. G., Pratt D. J., Endicott J. A., et al. 2002. Structure-based design of cyclin-dependent kinase inhibitors. Pharmacol Ther. 93(2-3): 125-133.
Day A.J., Canada F.J., Diaz J.C., et al. 2000. Dietary flavonoid and isoflavone glycosides are hydrolysed by the lactase site of lactase phlorizin hydrolase. FEBS Lett. 468 (223): 166-170.
Day A.J., DuPont M.S., Ridley S., et al. 1998. Deglycosylation of flavonoid and isoflavonoid glycosides by human small intestine and liver h-glucosidase activity. FEBS Lett. 436(1): 71-75.
Day A.J., Gee J. M., Dupontm S., et al. 2003. Absorption of quercetin-3-glucoside and quercetin- 4'-glucoside in the rat small intestine: the role of lactase phlorizin hydrolase and the sodium-dependent glucose transporter. Biochem. Pharmacol. 65(7): 1199-1206.
De Azevedo W.F. Jr, Mueller-Dieckmann H.J., Schulze-Gahmen U., et al. 1996. Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2, a cell cycle kinase. Proc. Natl. Acad. Sci. U. S. A. 93(7): 2735-2740.
Deschner E.E., Ruperto J., Wong G., et al. 1991. Quercetin and rutin as inhibitors of azoxymethanol-induced colonic neoplasia. Carcinogenesis. 12(7): 1193-1196.
Deschner E.E., Ruperto J.F., Wong G.Y., et al. 1993. The effect of dietary quercetin and rutin on AOM-induced acute colonic epithelial abnormalities in mice fed a high-fat diet. Nutr. Cancer. 20(3): 199-204.
Divisi D., Tommaso S. D., Salvemini S., et al. 2006. Diet and cancer. Acta. Biomed. 77(2): 118-123.
Donaldson M.S. 2004. Nutrition and cancer: A review of the evidence for an anti-cancer diet. Nutr. J. 3(19):1-21.
Donnini S., Finetti F., Lusini L., et al. 2006. Divergent effects of quercetin conjugates on angiogenesis. Br. J. Nutr. 95(5): 1016-1023.
Dragsted L.O.1998. Natural antioxidants in chemoprevention. Arch. Toxicol Suppl. 20: 209-226.
Du Y., Guo H., Lou H.X. 2007. Grape seed polyphenol protect cardiac cells from apoptosis via induction of endogenous antioxidant enzymes. J. Agric. Food Chem. 55(5): 1695-1701.
Duraj J., Zazrivcova K., Bodo J., et al. 2005. Flavonoid quercetin, but not apigenin or luteolin, induced apoptosis in human myeloid leukemia cells and their resistant variants. Neoplasma. Neoplasma. 52(4): 273-279.
Erhart L.M., Lankat-Buttgereit B., Schmidt H., et al. 2005. Flavone initiates a hierarchical activation of the caspase-cascade in colon cancer cells. Apoptosis. 10(3): 611-617.
Evan G.I., Vousden K.H. 2001. Proliferation, cell cycle and apoptosis in cancer. Nature. 411(6835): 342-348.
Fadeel B., Orrenius S. 2005. Apoptosis: a basic biological phenomenon with wide-ranging implications in human disease. J. Intern. Med. 258(6): 479-517.
Fan T.J., Han L.H., Cong R.S., et al. 2005. Caspase family proteases and apoptosis. Acta. Biochim. Biophys. Sin. (Shanghai). 37(11): 719-727.
Fang J., Xia C, Cao Z., et al. 2005. Apigenin inhibits VEGF and HIF-1 expression via PI3K/AKT/p70S6K1 and HDM2/p53 pathways. FASEB J. 19(3): 342-353.
Fenton J.I., Hord N.G. 2006. Stage matters: choosing relevant model systems to address hypotheses in diet and cancer chemoprevention research. Carcinogenesis. 27(5): 893-902.
Ferguson P.J., Kurowska E., Freeman D.J., et al. 2004. A flavonoid fraction from cranberry extract inhibits proliferation of human tumor cell lines. J. Nutr. 134(6): 1529-1535.
Fink B.N., Steck S.E., Wolff M.S., et al. 2007. Dietary flavonoid intake and breast cancer risk among women on Long Island. Am. J. Epidemiol. 165(5): 514-523
Flores E.R., Tsai K. Y., Crowley D. et al. 2002. p63 and p73 are required for p53-dependent apoptosis in response to DNA damage. Nature. 416(6880): 560-564.
Fotsis T., Pepper M.S., Aktas E., et al. 1997. Flavonoids .dietary derived inhibitors of cell proliferation and in vitro angiogenesis. Cancer Res. 57(14): 2916-2921.
Fridman J.S., Lowe S.W. 2003. Control of apoptosis by p53. Oncogene. 22(56): 9030-9040.
Galati G., Sabzevari O., Wilson J.X., et al. 2002. Prooxidant activity and cellular effects of the phenoxyl radicals of dietary flavonoids and other polyphenolics. Toxicology. 177(1): 91-104.
Garcia-Closas R., Agudo A., Gonzalez C.A., et al. 1998. Intake of specific carotenoids and flavonoids and the risk of lung cancer in women in Barcelona, Spain. Nutr. Cancer. 32(3): 154-158.
Garcia-Closas R., Gonzalez C, Agudo A., et al. 1999. Intake of specific carotenoids and flavonoids and the risk of gastric cancer in Spain. Cancer Causes Control. 10(1): 71-75.
Gates M.A., Tworoger S.S., Hecht J.L., et al. 2007. A prospective analysis of dietary flavonoid intake and epithelial ovarian cancer. Int. J. Cancer. 121(10): 2225-2232.
Graadolatto A., Canivenc-Lavier M.C., Basly J.P., et al. 2004. Metabolism of apigenin by liver phase I and phase II enzymes and by isolated perfused rat liver. Drug Metab. Dispos. 32 (1): 58-65.
Granado-Serrano A.B., Martin M.A., Bravo L., et al. 2006. Quercetin induces apoptosis via caspase activation, regulation of Bcl-2, and inhibition of PI-3-Kinase/Akt and ERK pathways in a human hepatoma cell line (HepG2). J. Nutr. 136(11): 2715-2721.
Granado-Serrano A.B., Martin M.A., Izquierdo-Pulido M., et al. 2007. Molecular mechanisms of (-)-epicatechin and chlorogenic acid on the regulation of the apoptotic and survival/proliferation pathways in a human hepatoma cell line. J. Agric. Food Chem. 55(5): 2020-2027.
Gschwendt M., Horn F., Kittstein W., et al. 1983. Inhibition of the calciumand phospholipid- dependent protein kinase activity from mouse brain cytosol by quercetin. Biochem. Biophys. Res. Commun. 117(2): 444-447.
Guadagno T.M., Newport J.W. 1996. Cdk2 kinase is required for entry into mitosis as a positive regulator of Cdc2-cyclin B kinase activity. Cell. 84(1): 73-82.
Gupta S., Afaq F., Mukhtar H. 2001. Selective growth-Inhibitory, cell cycled deregulatory and apoptotic response of apigenin in normal versus human prostate carcinoma cells. Biochem. Biophys. Res. Commun. 287(4): 914-920.
Gupta S., Afaq F., Mukhtar, H. 2002. Involvement of nuclear factor-kappa B, Bax and Bcl-2 in induction of cell cycle arrest and apoptosis by apigenin in human prostate carcinoma cells. Oncogene. 21(23): 3727-3738.
Guz R.N., Stermitz F.R., Jhonson J.B., et al. 2001. Flavonolignan and flavone inhibitors of a Staphylococcus aureus multidrug resistance pump: structure-activity relationships. J. Med. Chem. 44(2): 261-268.
Haddad A.Q., Venkateswaran V., Viswanathan L, et al 2006. Novel antiproliferative flavonoids induce cell cycle arrest in human prostate cancer cell lines. Prostate Cancer Prostatic Dis. 9(1): 68-76.
Han H.Y., Shan S., Zhang X., et al. 2007. Down-regulation of prostate specific antigen in LNCaP cells by flavonoids from the pollen of Brassica napus L. Phytomedicine. 14(5): 338-43.
Harborne J.B., Williams C.A. 2000. Advances in flavonoid research since 1992. Phytochemistry. 55(6): 481-504.
Hatch F.T., Lightstone F.C., Colvin M.E. 2000. Quantitative structure-activity relationship of flavonoids for inhibition of heterocyclic amine mutagenicity. Environ. Mol. Mutagen. 35(4): 279-299.
Haupt S., Berger M., Goldberg Z., et al. 2003. Apoptosis—the p53 network. J. Cell Sci. 116(pt 20): 4077-4085.
Heber D., Bowerman S. 2001. Applying science to changing dietary patterns. J. Nutr. 131(11 Suppl): 3078S-3081S.
Hecht S.S. 1999. Chemoprevention of cancer by isothiocyanates, modifiers of carcinogen metabolism. J. Nutr. 129(3): 768S-774S.
Hendrich A.B. 2006. Flavonoid-membrane interactions: possible consequences for biological effects of some polyphenolic compounds. Acta Pharmacol. Sin. 27(1): 27-40.
Heo M.Y., Lee S.J., Kwon C.H., et al. 1994. Anticlastogenic effects of galangin against bleomycin-induced chromosomal aberrations in mouse spleen lymphocytes. Mutat. Res. 311(2): 225-229.
Herr I., Debatin K.M. 2001. Cellular stress response and apoptosis in cancer therapy. Blood. 98(9): 2603-2614.
Hirvonen T., Virtamo J., Korhonen P., et al. 2001. Flavonol and flavone intake and the risk of cancer in male smokers (Finland). Cancer Causes Control. 12(9): 789-796.
Hollman P.C., de Vries J.H., van Leeuwen S.D., et al. 1995. Absorption of dietary quercetin glycosides and quercetin in healthy ileostomy volunteers. Am. J. Clin. Nutr. 62(6): 1276-1282.
Hong W.K., Sporn M.B. 1997. Recent advances in chemoprevention of cancer. Science. 278(5340): 1073-1077.
Hooijberg J.H., Broxterman H.J., Heijn M., et al. 1997. Modulation by (iso) flavoniods of the ATPase activity of the multidrug resistance protein. FEBS Lett. 413(2): 344-348.
Horinaka M., Yoshida T., Shiraishi T., et al. 2005. Luteolin induces apoptosis via death receptor 5 upregulation in human malignant tumor cells. Oncogene. 24(48): 7180-7189.
Horinaka M., Yoshida T., Shiraishi T., et al. 2005. The combination of TRAIL and luteolin enhances apoptosis in human cervical cancer HeLa cells. Biochem. Biophys. Res. Commun. 333 (3): 833-838.
Hsiao Y.C., Hsieh Y.S., Kuo W.H., et al. 2007. The tumor-growth inhibitory activity of flavanone and 2'-OH flavanone in vitro and in vivo through induction of cell cycle arrest and suppression of cyclins and CDKs. J. Biomed. Sci. 14(1): 107-119.
Hsu Y.L., Kuo P.L., Liu C.F., et al. 2004. Acacetin-induced cell cycle arrest and apoptosis in human non-small cell lung cancer A549 cells. Cancer Lett. 212(1): 53-60.
Human and Animal Cell Lines (http://www.biotech.ist.unige.it /cldb/cname-1c.html) Imai Y., Tsukahara S., Asada S., et al. 2004. Phytoestrogens/flavonoids reverse breast cancer resistance protein/ABCG2-mediated multidrug resistance. Cancer Res. 64(12): 4346-4352.
Innocente S.A., Lee J.M. 2005. p73 is a p53-independent, Sp1-dependent repressor of cyclin B1 transcription. Biochem. Biophys. Res. Commun. 329 (2): 713-718.
Ismail I.A., Kang K.S., Lee H.A., et al. 2007. Genistein-induced neuronal apoptosis and G2/M cell cycle arrest is associated with MDC1 up-regulation and PLK1 down-regulation. Eur. J. Pharmacol. 575(1-3): 12-20.
Jeffrey P.D., Russo A.A., Polyak K., et al. 1995. Mechanism of CDK activation related by the structure of cyclin A-cdk2 complex. Nature. 376(6538): 313-320.
Jin S., Antinore M.J, Lung F.D., et al. 2000. The GADD45 inhibition of Cdc2 kinase correlates with GADD45-mediated growth suppression. J. Biol. Chem. 275(22): 16602-16608.
Kal H.B., de Graaff E., Van Berkel A.H., et al. 1992. Responses of experimental rat tumours and a mouse colon tumour to flavone acetic acid. In Vivo. 6(1): 73-75.
Kanakis C.D., Tarantilis P.A., Polissiou M.G, et al. 2007. An overview of DNA and RNA bindings to antioxidant flavonoids. Cell Biochem. Biophys. 49(1): 29-36.
Kandaswami C, Perkins E., Soloniuk D.S., et al. 1991. Antiproliferative effects of citrus flavonoids on a human squamous cell carcinoma in vitro. Cancer Lett. 56 (2): 147-152.
Kawaii S., Tomono Y., Katase E., et al. 1999. Effect of citrus flavonoids on HL-60 cell differentiation. Anticancer Res. 19(2A): 1261-1269.
Khan T.H., Sultana S. 2006: Apigenin induces apoptosis in Hep G2 cells: Possible role of TNF-a and IFN-γ. Toxicology 217 (2-3): 206-212.
Kim D.H., Kim S.Y., Park S.Y., et al. 1999. Metabolism of quercitrin by human intestinal bacteria and its relation to some biological activities. Biol. Pharm. Bull. 22 (7): 749-751.
Kim M.J., Kim Y.J., Park H.J., et al. 2006. Apoptotic effect of red wine polyphenol on human colon cancer SNU-C4 cells. Food Chem. Toxicol. 44 (6): 898-902.
Kitagawa S. 2006. Inhibitory Effects of polyphenol on P-glycoprotein-mediated transport. Biol. Pharm. Bull. 29(1): 1-6.
Knekt P., Jarvinen R., Seppanen R., et al. 1997. Dietary flavonoids and the risk of lung cancer and other malignant neoplasms. Am. J. Epidemiol. 146(3): 223-230.
Knekt P., Kumpulainen J., Jarvinen R., et al. 2002. Flavonoid intake and risk of chronic diseases. Am. J. Clin. Nutr. 76(3): 560-568.
Knowles L.M., Zigrossi D.A., Tauber R.A., et al. 2000. Flavonoids suppress androgen-independent human prostate tumor proliferation. Nutr. Cancer. 38(1): 116-122.
Ko C.H., Shen S.C., Chen Y.C. 2004. Hydroxylation at C4V or C6 is essential for apoptosis- inducing activity of flavanones through activation of caspase-3 cascade and production of reactive oxygen species. Free Radical Biol. Med. 36(7): 897-910.
Ko C.H., Shen S.C., Lee T.J.F., et al. 2005. Myricetin inhibits matrix metalloproteinase- protein expression and enzyme activity in colorectal carcinoma cells. Mol. Cancer Ther. 4(2): 281-290.
Kobayakawa J., Sato Nishimori F., Moriyasu M., et al. 2004. G2-M arrest and antimitotic activity mediated by casticin, a flavonoid isolated from Viticis Fructus (Vitex rotundifolia Linne fil.) Cancer Lett. 208(1): 59-64.
Kobayashi T., Nakata T., Kuzumaki T. 2002. Effect of flavonoids on cell cycle progression in prostate cancer cells. Cancer Lett. 176(1): 17-23.
Kuntz S., Wenzel U., Daniel H. 1999. Comparative analysis of the effects of flavonoids on proliferation, cytotoxicity, and apoptosis in human colon cancer cell lines. Eur. J. Nutr. 38(3):133-142.
Kuo H.M., Chang L.S., Lin Y.L., et al. 2007. Morin inhibits the growth of human leukemia HL-60 cells via cell cycle arrest and induction of apoptosis through mitochondria dependent pathway. Anticancer Res. 27(1A): 395- 405.
Kuo S.M. 1996. Antiproliferative potency of structurally distinct dietary flavonoids on human colon cancer cells. Cancer Lett. 110(1-2): 41-48.
Lagergren L. 2005. Adenocarcinoma of oesophagus: what exactly is the size of the problem and who is at risk? Gut. 54(Suppl 1): il-i5.
Lam A.K.Y. 2000. Molecular biology of esophageal squamous cell carcinoma. Critical Reviews in Oncology/Hematology. 33(2): 71-90.
Layke J.C., Lopez P.P. 2006. Esophageal Cancer: A Review and Update. Am. Fam. Physician. 73: 2187-2194.
Lazze M.C., Savio M., Pizzala R., et al. 2004. Anthocyanins induce cell cycle perturbations and apoptosis in different human cell lines. Carcinogenesis. 25(8): 1427-1433.
Le Marchand L., Murphy S., Hankin J., et al. 2000. Intake of flavonoids and lung cancer. J. Natl. Cancer Inst. 92(2): 154-160.
Lee H.J., Wang C.J., Kuo H.C., et al. 2005. Induction apoptosis of luteolin in human hepatoma HepG2 cells involving mitochondria translocation of Bax/Bak and activation of JNK. Toxicology and Applied Pharmacology. 203(2): 124-131.
Lehrbach D.M., Nita M.E., Cecconello I. 2003. Molecular aspects of esophageal squamous cell carcinoma carcinogenesis. Clinical Genomics of Esophageal Cancer Group. 40(4): 256-261.
Leung H.W.C., Lin C.J., Hour M.J., et al. 2007. Kaempferol induces apoptosis in human lung non-small carcinoma cells accompanied by an induction of antioxidant enzymes. Food and Chemical Toxicology. 45(10): 2005-2013.
Leung H.W.C., Yang W.H., Lai M.Y., et al. 2007. Inhibition of 12-lipoxygenase during baicalein-induced human lung nonsmall carcinoma H460 cell apoptosis. Food and Chemical Toxicology. 45(3): 403-411.
Lim do Y, Jeong Y, Tyner A.L., et al. 2007. Induction of cell cycle arrest and apoptosis in HT-29 human colon cancer cells by the dietary compound luteolin. Am. J. Physiol. Gastrointest. 292(1): G66-75.
Lin J., Zhang S.M., Wu K. 2006. Flavonoid intake and colorectal cancer risk in men and women. Am. J. Epidemiol. 164(7): 644-651.
Lin Y.T., Hsiu S.L., Hou Y.C., et al. 2003. Degradation of flavonoid aglycones by rabbit, rat and human fecal flora. Biol. Pharm. Bull. 26(5): 747-751.
Lindenmeyer F., Li H., Menashi S., et al. 2001. Apigenin acts on the tumor cell invasion process and regulates protease production. Nutr. Cancer. 39(1): 139-147.
Liu L.Z., Fang J., Zhou Q., et al. 2005. Apigenin inhibits expression of vascular endothelial growth factor and angiogenesis in human lung cancer cells: implication of chemoprevention of lung cancer. Mol. Pharmacol. 68(10): 635-643.
Liu R.H. 2004. Potential synergy of phytochemicals in cancer prevention: mechanism of action. J. Nutr. 134(12 Suppl): 3479S-3485S.
Liu T., Xu Z. M., He Q. J., et al. 2007. Nitrogen-containing flavonoids as CDK1/Cyclin B inhibitors: Design, synthesis, and biological evaluation. Bioorganic & Medicinal Chemistry Letters. 17(1): 278-281.
Lopez-Lazaro M. 2002. Flavonoids as anticancer agents: structure-activity relationship study. Curr. Med. Chem. Anticancer Agents. 2(6): 691-714.
Lu X., Jung J., Cho H.J., et al. 2005. Fisetin inhibits the activities of cyclin-dependent kinases leading to cell cycle arrest in HT-29 human colon cancer cells. J. Nutr. 135(12): 2884-2890.
Luk S.C., Siu S.W., Lai C.K., et al. 2005. Cell cycle arrest by a natural product via G2/M checkpoint. Int. J. Med. Sci. 2(2): 64-69.
Mak P., Leung Y.K., Tang W.Y., et al. 2006. Apigenin suppresses cancer cell growth through ERβ. Neoplasia. 8(11): 896-904.
Makita H., Tanaka T., Fujitsuka H., et al. 1996. Chemoprevention of 4-nitraquinoline 1-oxide-induced rat oral carcinogenesis by the dietary flavonoids chalcone, 2-hydroxychalcone, and quercetin. Cancer Res. 56: 4904-4909.
Manach C., Morand C., Crespy V., et al. 1998. Quercetin is recovered in human plasma as conjugated derivatives which retain antioxidant properties. FEBS Lett. 426(3): 331-336.
Manach C., Morand C., Texier O., et al. 1997. Bioavailability of rutin and quercetin in rats. FEBS Lett. 409(1): 12-16.
Manach C., Scalbert A., Morand C., et al. 2004. Polyphenols: food sources and bioavailability. Am. J. Clin. Nutr. 79(5): 727-747.
Manthey JA, Guthrie N. 2002. Antiproliferative activities of citrus flavonoids against six human cancer cell lines. J. Agric. Food Chem. 50(21): 5837-5843.
Marchenko N.D., Zaika A., Moll U.M. 2000. Death signal-induced localization of p53 protein to mitochondria. A potential role in apoptotic signaling. J. Biol. Chem. 275(21): 16202-16212.
Martens S., Mithofer A. 2005. Flavones and flavone synthases. Phytochemistry. 66(20): 2399-2407.
Martin K.R. 2006. Targeting apoptosis with dietary bioactive agents. Exp. Biol. Med. 231(2): 117-129.
Matsui J., Kiyokawa N., Takenouchi H., et al. 2005. Dietary bioflavonoids induce apoptosis in human leukemia cells. Leuk. Res. 29(5): 573-581
Mayne S.T., Risch H.A., Dubrow R., et al. 2001. Nutrient intake and risk of subtypes of esophageal and gastric cancer. Cancer Epidemiol Biomarkers Prev. 10(10): 1055-1062
McCabe M.L., Dlamini Z. 2005. The molecular mechanisms of oesophageal cancer. Int. Immunopharmacol. 5(7-8): 1113-1130
Melino G., Bernassola F., Ranalli M., et al. 2004. p73 Induces apoptosis via PUMA transactivation and Bax mitochondrial translocation. J. Biol. Chem. 279(9): 8076-8083.
Middleton E., Kandaswami C, Theoharides T.C. 2000. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev. 52(4): 673-751.
Min K., Ebeler S.E. 2008. Flavonoid effects on DNA oxidation at low concentrations relevant to physiological levels. Food Chem. Toxicol. 46(1): 96-104
Miocinovic R., McCabe N.P., Keck R.W., et al. 2005. In vivo and in vitro effect of baicalein on human prostate cancer cells. Int. J. Oncol. 26 (1): 241-246.
Moll U.M., Slade N. 2004. p63 and p73 roles in development and tumor formation. Mol. Cancer Res. 2(7): 371-386.
Moore J.D., Yang J., Truant R., et al. 1999. Nuclear import of Cdk/cyclin complexes: identification of distinct mechanisms for import of Cdk2/cyclin E and Cdc2/cyclin B1. J. Cell Biol. 144(2): 213-224
Morand C, Manach C, Crespy V., et al. 2000. Quercetin 3-O-β-glucoside is better absorbed than other quercetin forms and is not present in rat plasma. Free Rad. Res. 33(5): 667-676.
Morley K.L., Ferguson P.J., Koropatnick J. 2007. Tangeretin and nobiletin induce G1 cell cycle arrest but not apoptosis in human breast and colon cancer cells. Cancer Lett. 251(1): 168-178.
Mu C., Jia P., Yan Z., et al. 2007. Quercetin induces cell cycle G1 arrest through elevating Cdk inhibitors p21 and p27 in human hepatoma cell line (HepG2). Methods Find Exp. Clin. Pharmacol. 29(3): 179-183
Murray T.J., Yang X.h., Sherr D.H. 2006. Growth of a human mammary tumor cell line is blocked by galangin, a naturally occurring bioflavonoid, and is accompanied by down-regulation of cyclins D3, E, and A. Breast Cancer Res. 8(2): R17
Mutoh M., Takahashi M., Fukuda K., et al. 2000. Suppression by flavonoids of cyclooxygenase-2 promoter-dependent transcriptional activity in colon cancer cells: structure-activity relationship. Jpn. J. Cancer Res. 91(7): 686-91.
Naik, H.R., Lehr, et al. 1994. An in vitro and in vivo study of antitumor effects of genistein on hormone refractory prostate cancer. Anticancer Res. 14(6B): 2617-2620.
Nair H.K., Rao K.V.K., Aalinkeel R., et al. 2004. Inhibition of prostate cancer cell colony formation by the flavonoid quercetin correlates with modulation of specific regulatory genes. Clin. Diagn. Lab. Immunol.. 11(1): 63-69
Nakadate T., Yamamoto S., Aizu E., et al. 1983. Effects of flavonoids and antioxidants on 12-O-tetradecanoyl-phorbol-13-acetate-caused epidermal ornithinedecarboxylase induction and tumor promotion in relation to lipoxygenase inhibition by these compounds. Gann. 75(3): 214-222.
Neuhouser M.L. 2004. Dietary flavonoids and cancer risk: evidence from human population studies. Nutr. Cancer. 50(1): 1-7.
Nguyen T.T., Tran E., Nguyen T., et al. 2004. The role of activated MEK-ERK pathway in quercetin-induced growth inhibition and apoptosis in A549 lung cancer cells. Carcinogenesis. 25(5): 647-659.
Nguyen T.T., Tran E., Ong C.K., et al. 2003. Kaempferol-Induced Growth Inhibition and Apoptosis in A549 Lung Cancer Cells Is Mediated by Activation of MEK-MAPK. J. Cell. Physiol. 197(1): 110-121.
Nielsen S.E., Breinholtv., Justesen U., et al. 1998. In vitro biotransfoumation of flavonoids by rat liver microsomes. Xenobiotica. 28(4): 389-401.
Nishino H., Nagao M., Fujiki H., et al. 1983. Role of flavonoids in suppressingthe enhancement of phospholipid metabolism by tumor promoters. Cancer Lett. 21(1): 1-8.
Nishino H., Naito E., Iwashima A., et al. 1984. Interaction between quercetin and Ca~(2+) calmodulin complex: Possible mechanism for anti-tumor-promoting action of the flavonoids. Gann. 75(4): 311-316.
Norman H. A., Go V. L., Butrum R.R. 2004. Review of the international research conference on food, nutrition, and cancer, 2004. J. Nutr. 134(12 Suppl): 3391S-3393S.
Nothlings U., Murphy S.P., Wilkens L.R., et al. 2007. Flavonols and pancreatic cancer risk: the multiethnic cohort study. Am. J. Epidemiol. 166(8): 924-931.
O'Leary K.A., Day A.J., Needs P.W., et al. 2001. Flavonoid glucuronides are substrates for human liver beta -glucuronidase. FEBS Lett. 503(1): 103-106.
O'Leary K.A., de Pascual-Tereasa S., Needs P.W., et al. 2004. Effect of flavonoids and Vitamin E on cyclooxygenase-2 (COX-2) transcription. Mutat .Res. 551 (1-2): 245-254.
Oh S.M., Chung K.H. 2004. Estrogenic activities of Ginkgo biloba extracts. Life Sci. 74(11): 1325-1335.
Oki T., Sowa Y., Hirose T., et al. 2004. Genistein induces Gadd45 gene and G2/M cell cycle arrest in the DU145 human prostate cancer cell line. FEBS Lett. 577(1-2): 55-59.
Olthof M.R., Hollman P.C., Vree T.B., et al. 2000. Bioavailabilities of quercetin-3-glucoside and quercetin-4'-glucoside do not differ in humans. J. Nutr. 130(5): 1200-1203.
Ong C.S., Tran E., Nguyen T.T., et al. 2004. Quercetin-induced growth inhibition and cell death in nasopharyngeal carcinoma cells are associated with increase in Bad and hypophosphorylated retinoblastoma expressions. Oncol. Rep. 11(3): 727-733.
Oniscu A., Sphyris N., Morris R.G., et al. 2004. p73a is a candidate effector in the p53 independent apoptosis pathway of cisplatin damaged primary murine colonocytes. J. Clin. Pathol. 57(5): 492-498.
Otake Y., Hsieh F., Walk T. 2002. Glucuronidation versus oxidation of the flavonoid galangin by human liver microsomes and heptocytes. Drug Metab. Dispos. 30(5): 576-581.
Pan M.H., Chen W.J., Lin-Shiau S.Y., et al. 2002. Tangeretin induces cell-cycle G1 arrest through inhibiting cyclin-dependent kinases 2 and 4 activities as well as elevating Cdk inhibitors p21 and p27 in human colorectal carcinoma cells. Carcinogenesis. 23(10): 1677-1684.
Parmar V.S., Jain R., Sharma S.K., et al. 1994. Anti-invasive activity of 3,7-dimethoxyflavone in vitro. J. Pharm. Sci. 83(9): 1217-1221.
Passamonti S., Vrhovsek U., Vanzo A., et al. 2003. The stomach as a site for anthocyanins absorption from food. FEBS Lett. 544(1-3): 210-213.
Peterson J., Lagiou P., Samoli E., et al. 2003. Flavonoid intake and breast cancer risk: a case-control study in Greece. Br. J. Cancer. 89(7): 1255-1259.
Pouget C, Lauthier E, Simon A., et al. 2001. Flavonoids: structural requirements for antiproliferative activity on breast cancer cells. Bioorg. Med. Chem. Lett. 11(24): 3095-3097.
Pucci B., Kasten M., Giordano A., 2000. Cell cycle and apoptosis. Neoplasia. 2(4): 291-299.
Ramos S. 2007. Effects of dietary flavonoids on apoptotic pathways related to cancer chemoprevention. J. Nutr. Biochem. 18(7): 427-442.
Ramos S., Alia M., Bravo L., et al. 2005. Comparative effects of food-derived polyphenol on the viability and apoptosis of a human hepatoma cell line (HepG2). J. Agric. Food Chem. 53(4): 1271-1280.
Redrejo-Rodriguez M., Tejeda-Cano A., Pinto M.C., et al. 2004. Lipoxygenase inhibition by flavonoids: semiempirical study of the structure-activity relation. Journal of Molecular Structure (Theochem). 674 (1-3);. 121-124.
Reed J.C. 2000. Mechanisms of Apoptosis. Am. J. Pathol. 157(5): 1415-1430.
Ren W., Qiao Z., Wang H., et al. 2003. Flavonoids: promising anticancer agents. Med. Res. Rev. 23(4): 519-534.
Rosenkranz H.S., Thampatty B.P. 2003. SAR: flavonoids and COX-2 inhibition. Oncol Res. 13(12): 529-535.
Rossi M., Garavello W., Talamini R., et al. 2007. Flavonoids and the risk of oral and pharyngeal cancer: a case-control study from Italy. Cancer Epidemiol. Biomarkers. Prev. 16(8): 1621-1625.
Rossi M., Negri E., Talamini R., et al. 2006. Flavonoids and colorectal cancer in Italy. Cancer Epidemiol. Biomarkers Prev. 15(8): 1555-1558.
Rusak G., Gutzeit H., Muller J. 2005. Structurally related flavonoids with antioxidative properties differentially affect cell cycle progression and apoptosis of human acute leukemia cells. Nutrition Research. 25(2): 143-155.
Russo G. L. 2007. Ins and outs of dietary phytochemicals in cancer chemoprevention. Biochem. Pharmacol. 74(4): 533-544.
Russo M., Palumbo R., Tedesco 1., et al. 1999. Quercetin and anti-CD95 (Fas/Apol) enhance apoptosis in HPB-ALL cell line. FEBS. 462(3): 322-328.
Sagar S.M., Yance D., Wong R.K. 2006. Natural health products that inhibit angiogenesis: a potential source for investigational new agents to treat cancer-part 2. Curr. Oncol.l3(3): 99-107.
Salucci M., Stivala L.A., Maiani G., et al. 2002. Flavonoids uptake and their effect on cell cycle of human colon adenocarcinoma cells (Caco2). Br. J. Cancer. 86 (10): 1645-1651.
Sasaki M., Nakamura H., Tsuchiya S., et al. 2007. Quercetin-induced PC12 cell death accompanied by caspase-mediated DNA fragmentation. Biol. Pharm. Bull. 30(4): 682-686.
Scambia G., Ranelletti F.O., Panici P.B., et al. 1994. Quercetin potentiates the effect of adriamycin in a multidnig-resistant MCF-7 human breast-cancer cell line: P-glycoprotein as a possible target. Cancer Chemother. Pharmacol. 34 (6): 459-464.
Schneider H., Blaut M. 2000. Anaerobic degradation of flavonoids by eubacterium ramulus. Arch. Microbiol. 173(1): 71-75.
Schoefer L., Mohan R., Schwiertza., et al. 2003. Anaerobic degradation of flavonoids by clostridium orbiscindens. Appl Environ Microbiol. 69(10): 5849-5854.
Schwartz G.K., Shah M.A. 2005. Targeting the Cell Cycle: A New Approach to Cancer Therapy. J .Clin.Oncol. 23(36): 9408-9421.
Senderowicz A. M. 1999. Flavopiridol: the first cyclin-dependent kinase inhibitor in human clinical trials. Invest New Drugs. 17(3): 313-320.
Shapiro G. I., Koestner D.A., Matranga C. B., et al. 1999. Flavopiridol induces cell cycle arrest and p53-independent apoptosis in non-small cell lung cancer cell lines. Clin.Cancer Res. 5(10): 2925-2938.
Sharma Y., Agarwal C, Singh A.K., et al. 2001. Inhibitory effect of silibinin on ligand binding to erbB1 and associated mitogenic signaling, growth, and DNA synthesis in advanced human prostate carcinoma cells. Mol. Carcinog. 30(4): 224-236.
Shen S.C., Ko C.H., Tseng S.W., et al. 2004. Structurally related antitumor effects of flavanones in vitro and in vivo: involvement of caspase 3 activation, p21 gene expression, and reactive oxygen species production. Toxicol. Appl. Pharmacol. 197(2): 84-95.
Shon Y.H., Park S.D., Nam K.S. 2006. Effective chemopreventive activity of genistein against human breast cancer cells. J. Biochem. Mol. Biol. Jul. 39(4): 448-451.
Shukla S. Gupta S. 2004. Molecular mechanisms for apigenin-induced cell-cycle arrest and apoptosis of hormone refractory human prostate carcinoma DU145 cells. Mol. Carcinog. 39(2): 114-126.
Shukla S., Gupta S. 2006. Molecular targets for apigenin-induced cell cycle arrest and apoptosis in prostate cancer cell xenograft. Mol. Cancer Ther. 5(4): 843 - 852.
Shukla S., Gupta S. 2007. Apigenin-induced cell cycle arrest is mediated by modulation of MAPK, PI3K-Akt, and loss of Cyclin D1 associated retinoblastoma dephosphorylation in human prostate cancer cells. Cell Cycle. 6(9): 1102-1114.
Singh R.P., Agarwal R. 2006. Natural flavonoids targeting deregulated cell cycle progression in cancer cells. Curr. Drug Targets. 7(3): 345-354.
Singh R.P., Agrawal P., Yim D., et al. 2005. Acacetin inhibits cell growth and cell cycle progression, and induces apoptosis in human prostate cancer cells: structure-activity relationship with linarin and linarin acetate. Carcinogenesis. 26(4): 845-854.
Singh R.P., Dhanalakshmi S., Agarwal R. 2002. Phytochemicals as cell cycle modulators—a less toxic approach in halting human cancers. Cell Cycle. 1(3): 156-161.
Smits V.A., Klompmaker R., Vallenius T., et al. 2000. p21 inhibits Thrl61 phosphorylation of Cdc2 to enforce the G2 DNA damage checkpoint. J. Biol. Chem. 275(39): 30638-30643.
Spencer J.P., Abd-el-Mohsen M.M., Rice-Evans C. 2004. Cellular uptake and metabolism of flavonoids and their metabolites: implications for their bioactivity. Arch. Biochem. Biophys. 423(1): 148-161.
Stark G.R., Taylor W.R. 2004. Analyzing the G2/M checkpoint. Methods Mol. Biol. 280: 51-82.
Stefani E.D., Boffetta P., Deneo-Pellegrini H., et al. 1999. Dietary antioxidants and lung cancer risk: a case-control study in Uruguay. Nutr. Cancer. 34(1): 100-110.
Steinmetz K.A., Potter J.D. 1996. Vegetables, fruit, and cancer prevention: a review. J. Am. Diet Assoc. 96(10): 1027-1039.
Stiewe T., Putzer B. M. 2001. p73 in apoptosis. Apoptosis. 6(6): 447-452.
Stiewe T., Putzer B. M. 2002. Role of p73 in malignancy: tumor suppressor or oncogene? Cell Death Differ. 9(3): 237-245.
Surh Y.J., 2003. Cancer chemoprevention with dietary phytochemicals.Nat. Rev. cancer. 3(10): 768-780.
Takagaki N., Sowa Y., Oki T., et al. 2005. Apigenin induces cell cycle arrest and p21/WAF1 expression in a p53-independent pathway. Int. J. Oncol. 26(1): 185-189.
Takahashi T., Kobori M., Shinmoto H., et al..1998. Structure-activity relationships of flavonoids and the induction of granulocytic- or monocytic-differentiation in HL60 human myeloid leukemia cells. Biosci.. Biotechnol. Biochem. 62(11): 2199-2204.
Takizawa C.G., Weis K, Morgan D.O., 1999. Ran-independent nuclear import of cyclin B1-Cdc2 by importin beta. Proc. Natl. Acad. Sci. USA. 96(14): 7938-7943.
Tanaka T., Makita H., Ohnishi M., et al. 1997. Chemoprevention of 4-nitroquinoline-1-oxide-induced oral carcinogenesis in rats by flavonoids diosmin and hesperidin, each alone and in combination. Cancer Res. 57(2): 246-252.
Tatsuta A., Iishi H., Baba M., et al. 2000. Suppression by apigenin of peritoneal metastasis of intestinal adenocarcinomas induced by azoxymethane in Wistar rats. Clin. Exp. Metastasis. 18(8): 657-662.
Taylor W.R., Stark G.R. 2001. Regulation of the G2/M transition by p53. Oncogene. 20(15): 1803-1815.
Theodoratou E., Kyle J.,. Cetnarskyj R., et al. 2007. Dietary flavonoids and the risk of colorectal cancer. Cancer Epidemiol. Biomarkers Prev. 16(4): 684-693.
Torkin R., Lavoie J.F., Kaplan D.R., et al. 2005. Induction of caspase-dependent, p53-mediated apoptosis by apigenin in human neuroblastoma. Mol. Cancer Ther. 4(1): 1-11.
Tyagi A., Agarwal C, Harrison G., et al. 2004. Silibinin causes cell cycle arrest and apoptosis in human bladder transitional cell carcinoma cells by regulating CDKI-CDK-cyclin cascade, and caspase 3 and PARP cleavages. Carcinogenesis. 25(9): 1711-1720.
Tyagi A., Bhatia N., Condon M.S., et al. 2002. Antiproliferative and apoptotic effects of silibinin in rat prostate cancer cells. Prostate. 53(3): 211-217.
Ujiki M.B., Ding X.Z., Salabat M.R., et al. 2006. Apigenin inhibits pancreatic cancer cell proliferation through G2/M cell cycle arrest. Mol. Cancer. 76 (5): 1-8.
Varghese L., Agarwal G.Tyagi A., et al. 2005. Silibinin efficacy against human hepatocellular carcinoma. Clin. Cancer Res. 11(23): 8441-8448.
Vargo M.A., Voss O.H., Poustka F., et al. 2006. Apigenin-induced-apoptosis is mediated by the activation of PKCd and caspases in leukemia cells. Biochem. Pharmacol. 72(6): 681-692.
Vauzour D., Vafeiadou K., Rice-Evans C., et al. 2007. Inhibition of cellular proliferation by the genistein metabolite 5,7,3',4'-tetrahydroxyisoflavone is mediated by DNA damage and activation of the ATR signalling pathway. Arch. Biochem. Biophys. 468(2): 159-166.
Veeriah S., Kautenburger T., Habermann N., et al. 2006. Apple flavonoids inhibit growth of HT29 human colon cancer cells and modulate expression of genes involved in the biotransformation of xenobiotics. Mol. Carcinog. 45(3): 164-174.
Versantvoort C.H., Rhodes T., Twentyman P.R. 1996. Acceleration of MRP-associated efflux of rhodamine 123 by genistein and related compounds. Br. J. Cancer. 74(12): 1949-1954.
Vidal A., Koff A. 2000. Cell-cycle inhibitors: three families united by a common cause. Gene. 247(1-2): 1-15.
Vijayababu M., Kanagaraj P., Arunkumar A., et al. 2005. Quercetin-induced growth inhibition and cell death in prostatic carcinoma cells (PC-3) are associated with increase in p21 and hypophosphorylated retinoblastoma proteins expression. J. Cancer Res. Clin. Oncol. 131(11): 765-771.
Virgili F., Acconcia F., Ambra R., et al. 2004. Nutritional flavonoids modulate estrogen receptor alpha signaling. IUBMB Life. 56(3): 145-151.
Vousden K.H. 2006. Outcomes of p53 activation-spoilt for choice. J. Cell Sci.119 (24): 5015-5020.
Walgren R.A., Lin J.T., Kinne R.K., et al. 2000. Cellular uptake of dietary flavonoid quercetin 4'-beta-glucoside by sodium-dependent glucose transporter SGLT1. J Pharmacol. Exp. Ther. 294 (3): 837-843.
Walgrenra R.A., Karnaky K.J.Jr., Lindenmayer G.E., et al. 2000. Efflux of dietary flavonoid quercetin-4'-beta-glucoside across human intestinal Caco-2 cell monolayers by apical multidrug resistance-associated protein-2. J. Pharmacol. Exp.Ther. 294(3): 830-836.
Walle T. 2004. Absorption and metabolism of flavonoids. Free Radic. Biol. Med. 36(7): 829-837.
Walle T. 2007. Methoxylated flavones, a superior cancer chemopreventive flavonoid subclass? Semin. Cancer Biol. 17(5): 354-362.
Walle T., Otake Y., Walle U. K., et al. 2000. Quercetin glucosides are completely hydrolyzed in ileostomy patients before absorption. J. Nutr. 130(11): 2658-2661.
Wang I.K., Lin-Shiau S.Y., Lin J.K., 1999. Induction of apoptosis by apigenin and related flavonoids through cytochrome c release and activation of caspase-9 and caspase-3 in leukaemia HL-60 cells. Eur. J. Cancer. 35(10): 1517-1525.
Wang W., VanAlstyne P.C., Irons K.A., et al. 2004. Individual and interactive effects of apigenin analogs on G2/M cell-cycle arrest in human colon carcinoma cell lines. Nutr. Cancer. 48(1): 106-114.
Wargovich M.J., Eng V.W., Newmark H.L. 1985. Inhibition by plant phenols of benzo[a]pyrene- induced nuclear aberrations in mammalian intestinal cells: A rapid in vivo assessment method. Food Chem. Toxicol. 23(1): 47-49.
Wartenberg M., Budde P., De Marees M., et al. 2003. Inhibition of tumor-induced angiogenesis and matrix-metalloproteinase expression in confrontation cultures of embryoid bodies and tumor spheroids by plant ingredients used in traditional Chinese medicine. Lab. Invest. 83 (1): 87-98.
Watanabe C.M., Wolffram S., Ader P., et al. 2001. The in vivo neuromodulatory effects of the herbal medicine ginkgo biloba. Proc. Natl. Acad. Sci.USA. 98 (12): 6577-6580.
Way T.D., Kao M.C., Lin J.K. 2004. Apigenin induces apoptosis through proteasomal degradation of HER2/neu in HER2/neu-overexpressing breast cancer cells via the Phosphatidylinositol 3-Kinase/Akt-dependent pathway. J. Biol. Chem. 279(6): 4479-4489.
WCRF/AICR: Food, nutrition and the prevention of cancer: a global perspective: World Cancer Research Fund /American Institute for Cancer Research 1997.
Wen X., Walle T. 2006. Methylated Flavonoids have greatly improved intestinal absorption and metabolic stability. Drug Metab. Dispos. 34(10): 1786-1792.
Weng M.S., Ho Y.S., Lin J.K. 2005. Chrysin induces G1 phase cell cycle arrest in C6 glioma cells through inducing p21Wafl/Cipl expression: involvement of p38 mitogen-activated protein kinase. Biochem. Pharmacol. 69 (12): 1815-1827.
Wenzel U., Kuntz S., Brendel M.D., et al. 2000. Dietary flavone is a potent apoptosis inducer in human colon carcinoma cells. Cancer Res. 60(14): 3823-3831.
Wenzel U., Nickel A., Daniel H. 2005. Increased mitochondrial palmitoylcarnitine/ carnitine countertransport by flavone causes oxidative stress and apoptosis in colon cancer cells. Cell Mol. Life Sci. 62(24): 3100-3105.
Westfall M.D., Pietenpol J.A. 2004. p63: molecular complexity in development and cancer. Carcinogenesis. 25(6): 857-864.
Willett W. C. 2000. Diet and cancer. Oncologist. 5(5): 393-404.
Wolffram S., Block M., Ader P. 2002. Quercetin-3-glucoside is transported by the glucose carrier SGLT1 across the brush border membrane of rat small intestine. J. Nutr. 132(4): 630-635.
Woo K.J., Jeong Y.J., Park J.W., et al. 2004. Chrysin-induced apoptosis is mediated through caspase activation and Akt inactivation in U937 leukemia cells. Biochem. Biophys. Res. Commun. 325 (4): 1215-1222.
Yanez J., Vicente V, Alcaraz M., et al. 2004. Cytotoxicity and antiproliferative activities of several phenolic compounds against three melanocytes cell lines: relationship between structure and activity. Nutr. Cancer. 49(2): 191-199.
Yang J.H., Hsia T.C., Kuo H.M., et al. 2006. Inhibition of lung cancer cell growth by quercetin glucuronides via G2/M arrest and induction of apoptosis. Drug Metab. Dispos. 34(2): 296-304.
Yi W., Fischer J., Krewer G., et al. 2005. Phenolic compounds from blueberries can inhibit colon cancer cell proliferation and induce apoptosis. J. Agric. Food Chem. 53(18): 7320-7329.
Yin F., Giuliano A.E., Law R.E., et al. 2001. Apigenin inhibits growth and induces G2/M arrest by modulating cyclin-CDK regulators and ERK/MAP kinase activation in breast carcinoma cells. Anticancer Res. 21(1A): 413-420.
Yoshida T., Maeda A., Horinaka M., et al. 2005. Quercetin induces gadd45 expression through a p53-independent pathway. Oncol. Rep. 14(5): 1299-1303.
Yoshimizu N., Otani Y., Saikawa Y., et al. 2004. Anti-tumour effects of nobiletin, a citrus flavonoid, on gastric cancer include: antiproliferative effects, induction of apoptosis and cell cycle deregulation. Aliment Pharmacol. Ther. 20(Suppl 1): 95-101.
Zava D.T., Duwe G 1997. Estrogenic and antiproliferative properties of genistein and other flavonoids in human breast cancer cells in vitro. Nutr. Cancer. 27(1): 31-40.
Zhan Q., Antinore M.J:, Wang X.W., et al. 1999. Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45. Oncogene. 18(18): 2892-2900.
Zhang H., Chen S.H., Li Y.M. 2004. Epidemiological investigation of esophageal carcinoma. World J. Gastroenterol. 10(12): 1834-1835.
Zhang Q., Zhao X.H., Wang Z.J. 2008. Flavones and flavonols exert cytotoxic effects on a human oesophageal adenocarcinoma cell line (OE33) by causing G2/M arrest and inducing apoptosis. Food Chem Toxicol. 46(6): 2042-2053
Zhang S., Yang X., Morris M.E. 2004. Flavonoids Are Inhibitors of Breast Cancer Resistance Protein (ABCG2)-Mediated Transport. Mol. Pharmacol. 65(5): 1208-1216.
Zhang T., Chen X., Qu L, et al. 2004. Chrysin and its phosphate ester inhibit cell proliferation and induce apoptosis in Hela cells. Bioorg. Med. Chem.12 (23): 6097-6105.
Zhang X.M., Chen J., Xia Y.G., et al 2005. Apoptosis of murine melanoma B16-BL6 cells induced by quercetin targeting mitochondria, inhibiting expression of PKC-alfa and translocating PKC-delta. Cancer Chemother. Pharmacol. 55(3): 251-262.
Zhang Y., Talalay P. 1994. Anticarcinogenic activities of organic isothiocyanates: chemistry and mechanisms. Cancer Res. 54(7 Suppl): 1976s-1981s.
Zheng P.W., Chiang L.C., Lin C.C. 2005. Apigenin induced apoptosis through p53-dependent pathway in human cervical carcinoma cells. Life Sci. 76 (12): 1367-1379.
Zi X., Agarwal R. 1999. Silibinin decreases prostate-specific antigen with cell growth inhibition via G1 arrest, leading to differentiation of prostate carcinoma cells: implications for prostate cancer intervention. Proc. Natl. Acad. Sci. USA. 96(13): 7490-7595.
Zi X., Grasso A.W., Kung H.J., et al. 1998. A flavonoid antioxidant, silymarin, inhibits activation of erbB1 signaling and induces cyclin-dependent kinase inhibitors, Gl arrest, and anticarcinogenic effects in human prostate carcinoma DU145 cells. Cancer Res. 58(9): 1920-1929.
Zi X., Zhang J., Agarwal R., et al 2000. Silibinin up-regulates insulin-like growth factor-binding protein 3 expression and inhibits proliferation of androgen-independent prostate cancer cells .Cancer Res. 60(20): 5617-5620.
常徽,糜漫天.2006.植物黄酮抗肿瘤研究进展.国外医学卫生学分册.33(5):296-300.
陈业高.2004.植物化学成分.第一版.化学工业出版社.172-217.
高昕,王喜军.2005.黄酮类化合物抗肿瘤作用研究进展.中医药信息.22(5):33-34.
黄华艺,查锡良.2002.黄酮类化合物抗肿瘤作用研究进展.中国新药与临床杂志.21(7):428-433.
李荣,李俊.2005.黄酮类化合物药理活性及其构效关系研究进展.安徽医药.9(7):481-483.
刘舒,韩静,王绿娅.2004.黄酮、异黄酮药物抑制肿瘤细胞增殖作用的最新进展.中国药学杂志.39(1):4-7.
裴利宽,郭宝林.2006.黄酮类化合物吸收和代谢研究进展.中国药学杂志.41(8):568-572.
施明.2001.类黄酮抗肿瘤作用的研究进展.国外医学卫生学分册.28(2):96-99.
汤立建,赵良才,李庆林等.2007.黄芩黄酮类成分抗肿瘤作用及机制研究进展.中国中药杂志.32(1):21-24.
张汆,阚建全,陈宗道.2003.生物类黄酮抗癌作用研究进展.中国野生植物资源.22(4):8-11.
张玉霞,喻伦银,刘铭球.2001.细胞周期调控研究进展.国外医学遗传学分册.24(5):262-266.
钟晓刚,吴凯南.2001.槲皮素逆转肿瘤多药耐药的研究进展.国外医学肿瘤学分册.28(3):202-204.
朱会平.2006.黄酮类化合物促进癌细胞凋亡的分子机理研究进展.生物技术通讯.17(3):455-456.
Agarwal C.,Singh R.P.,Dhanalakshmi S.,et al.2003.Silibinin upregulates the expression of cyclin-dependent kinase inhibitors and causes cell cycle arrest and apoptosis in human colon carcinoma HT-29 cells.Oncogene.22(51):8271-8282.
Agnero M.F.,Facchinetti M.M.,Sheleg Z.,et al.2005.Phenoxodiol,a novel isoflavone,induces G1 arrest by specific loss in cyclin-dependent kinase 2 activity by p53-independent induction of p21WAF1/CIP1.Cancer Res.65(8):3364-3373.
Ahn Y.M.,Vogeti L.,Liu C.Jing.,et al.2007.Design,synthesis,and antiproliferative and CDK2-cyclin:A inhibitory activity of novel flavopiridol analogues.Bioorg.Med.Chem.15(2):702-713.
Aligiannis N.,Mitaku S.,Mitrocotsa D.,et al.2001.Flavonoids as cycline-dependent kinase inhibitors:inhibition of cdc 25 phosphatase activity by flavonoids belonging to the quercetin and kaempferol series.Planta.Med.67(5):468-470.
American Dietetic Association 1995.Position of the American Dietetic Association:phytochemicals and functional foods.J.Am.Diet Assoc.95(4):493-496.
Arts I.C.,Sesinka L.,Faassen-Peters M.,et al.2004.The type of sugar moiety is a major determinant of the small intestinal uptake and subsequent biliary excretion of dietary quercetin glycosides. Br. J. Nutr. 91(6): 841-847.
Atkinson C, Berman S., Humbert O., et al. 2004. In vitro incubation of human feces with daidzein and antibiotics suggests interindividual differences in the bacteria responsible for equol production. J. Nutr. 134(3): 596-599.
Bagli E., Stefaniotou M., Morbidelli L., et al. 2004. Luteolin inhibits vascular endothelial growth factor-induced angiogenesis; inhibition of endothelial cell survival and proliferation by targeting Phosphatidylinositol 3' -kinase activity. Cancer Research. 64(21): 7936-7946.
Beecher G R. 2003. Overview of dietary flavonoids: nomenclature, occurrence and intake. J. Nutr. 133(10): 3248S-3254S.
Bestwick C.S., Milne L., Duthie S.J. 2007. Kaempferol induced inhibition of HL-60 cell growth results from a heterogeneous response, dominated by cell cycle alterations. Chem. Biol. Interact. 170(2): 76-85.
Bingham S., Riboli E. 2004. Diet and cancer-the European prospective investigation into cancer and nutrition. Nature Reviews. 4(3): 206-215.
Birt D.F., Hendrich S., and Wang W. 2001. Dietary agents in cancer prevention: flavonoids and isoflavonoids. Pharmacol Ther. 90(2-3): 157-177.
Birt D.F., Mitchell D., Gold B., et al. 1997. Inhibition of ultraviolet light induced skin carcinogenesis in SKH-1 mice by apigenin, a plant flavonoid. Anticancer Res. 17(1A): 85-91.
Bloch A. S. 2000. Phytochemicals and functional foods for cancer risk reduction. Top Clin Nutr. 15(2): 24-28.
Block G., Patterson B., Subar A. 1992. Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Nutr. Cancer. 18(1): 1-29.
Bokkenheuser V.D., Shackleton C.H.L., Winter J. 1987. Hydrolysis of dietary flavonoid glycosides by strains of intestinal Bacteroides from humans. Biochem J. 248(3): 953-956.
Bosetti C, Rossi Marta., McLaughlin J.K., et al. 2007. Flavonoids and the risk of renal cell carcinoma. Cancer Epidemiol Biomarkers Prev. 16(1): 98-101.
Bosetti C, Spertini L., Parpinel M., et al. 2005. Flavonoids and breast cancer risk in Italy. Cancer Epidemiol Biomarkers Prev. 14(4): 805-808.
Boulaire J, Fotedar A, Fotedar R. 2000. The functions of the cdk-cyclin kinase inhibitor p21WAF1. Pathol. Biol. (Paris). 48(3): 190-202.
Bowey E., Adlercreutz H., Rowland I. 2003. Metabolismof isoflavonesand lignans by the gut microflora: a study in germ-free and human flora associated rats. Food Chem. Toxicol. 41(5): 631-636.
Bracke M.E., Vyncke B.M., Van Laebeke N.A., et al. 1989. The flavonoid tangeretin inhibits invasion of M04 mouse cells into embryonic chick heart in vitro. Clin. Exp. Metastasis. 7(3): 283-300.
Braune A., Gutschow M., Engst W., et al. 2001. Degradation of quercetin and luteolin by eubacterium ramulus. Appl. Environ. Microbiol. 67(12): 5558-5567.
Brown J.M., Wouters B.G. 1999. Apoptosis, p53, and tumor cell sensitivity to anticancer agents. Cancer Res. 59(7): 1391-1399.
Brusselmans K., Vrolix R., Verhoeven G., et al. 2005. Induction of cancer cell apoptosis by flavonoids is associated with their ability to inhibit fatty acid synthase activity. J. Biol. Chem. 280(7): 5636-5645.
Casagrande F., Darbon J.M. 2001. Effects of structurally related flavonoids on cell cycle progression of human melanoma cells: regulation of cyclin-dependent kinases CDK2 and CDK1. Biochem. Pharmacol. 61(10): 1205-1215.
Cayrol C, Knibiehler M., Ducommun B. 1998. p21 binding to PCNA causes G1 and G2 cell cycle arrest in p53-deficient cells. Oncogene. 16(3): 311-320.
Chan F. L., Choi H.L., Chen Z.Y., et al. 2000. Induction of apoptosis in prostate cancer cell lines by a favonoid, baicalin. Cancer Lett. 160(2): 219-228.
Chan T.A., Hermeking H., Lengauer C, et al. 1999. 14-3-3 Sigma is required to prevent mitotic catastrophe after DNA damage. Nature. 401(6753): 616-620.
Chan T.S., Galati G, Pannala A.S., et al. 2003. Simultaneous detection of the antioxidant and pro-oxidant activity of dietary polyphenolics in a peroxidase system. Free Radic. Res. 37(7): 787-794.
Chang J., Hsu Y, Kuo P., et al. 2005. Increase of Bax/Bcl-XL ratio and arrest of cell cycle by luteolin in immortalized human hepatoma cell line. Life Sciences. 76(16): 1883-1893.
Chang K.L., Kung M.L., Chow N.H., et al. 2004. Genistein arrests hepatoma cells at G2/M phase: involvement of ATM activation and upregulation of p21wafl/cipl and Weel. Biochem. Pharmacol. 67(4): 717-26.
Chen K.H., Weng M.S., Lin J.K. 2007. Tangeretin suppresses IL-1B-induced cyclooxygenase (COX)-2 expression through inhibition of p38 MAPK, JNK, and AKT activation in human lung carcinoma cells. Biochem. Pharmacology. 73(2): 215-227.
Chiang L.C., Ng L.T., Lin I.C., et al. 2006. Anti-proliferative effect of apigenin and its apoptotic induction in human Hep G2 cells. Cancer Letters. 237(2): 207-214.
Cohen G.M. 1997. Caspases: the executioners of apoptosis. Biochem. J. 326( Pt 1): 1-16.
Compte, G., Daskiewicz, J.B., Bayet, C., et al. 2001. C-Isoprenylation of flavonoids enhances binding affinity toward P-glycoprotein and modulation of cancer cell chemoresistance. Med. Chem. 44(5): 763-768.
Conseil, G., Baubichon-Cortay, H., Dayan, G., et al. 1998. Flavonoids: a class of modulators with bifunctional interactions at vicinal ATP- and steroid-binding sites on mouse P-glycoprotein. Proc. Natl. Acad. Sci. U. S. A. 95(17): 9831-9836.
Cooke D., Steward W.P., Gescher A.J., et al. 2005. Anthocyans from fruits and vegetables-Does bright colour signal cancer chemopreventive activity? Eur. J. Cancer. 41(13): 1931-1940.
Cummings J. H., Bingham S. A. 1998. Diet and the prevention of cancer. B.M.J. 317(7173): 1636-1640.
Darragh J., Hunter M., Pohler E., et al. 2006. The calcium-binding domain of the stress protein SEP53 is required for survival in response to deoxycholic acid-mediated injury. FEBS J. 273(9): 1930-1947.
Das S., Rosazza J.P. 2006. Microbial and enzymatic transformations of flavonoids. J. Nat. Prod. 69(3): 499-508.
Davies T. G., Pratt D. J., Endicott J. A., et al. 2002. Structure-based design of cyclin-dependent kinase inhibitors. Pharmacol Ther. 93(2-3): 125-133.
Day A.J., Canada F.J., Diaz J.C., et al. 2000. Dietary flavonoid and isoflavone glycosides are hydrolysed by the lactase site of lactase phlorizin hydrolase. FEBS Lett. 468 (223): 166-170.
Day A.J., DuPont M.S., Ridley S., et al. 1998. Deglycosylation of flavonoid and isoflavonoid glycosides by human small intestine and liver h-glucosidase activity. FEBS Lett. 436(1): 71-75.
Day A.J., Gee J. M., Dupontm S., et al. 2003. Absorption of quercetin-3-glucoside and quercetin- 4'-glucoside in the rat small intestine: the role of lactase phlorizin hydrolase and the sodium-dependent glucose transporter. Biochem. Pharmacol. 65(7): 1199-1206.
De Azevedo W.F. Jr, Mueller-Dieckmann H.J., Schulze-Gahmen U., et al. 1996. Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2, a cell cycle kinase. Proc. Natl. Acad. Sci. U. S. A. 93(7): 2735-2740.
Deschner E.E., Ruperto J., Wong G., et al. 1991. Quercetin and rutin as inhibitors of azoxymethanol-induced colonic neoplasia. Carcinogenesis. 12(7): 1193-1196.
Deschner E.E., Ruperto J.F., Wong G.Y., et al. 1993. The effect of dietary quercetin and rutin on AOM-induced acute colonic epithelial abnormalities in mice fed a high-fat diet. Nutr. Cancer. 20(3): 199-204.
Divisi D., Tommaso S. D., Salvemini S., et al. 2006. Diet and cancer. Acta. Biomed. 77(2): 118-123.
Donaldson M.S. 2004. Nutrition and cancer: A review of the evidence for an anti-cancer diet. Nutr. J. 3(19):1-21.
Donnini S., Finetti F., Lusini L., et al. 2006. Divergent effects of quercetin conjugates on angiogenesis. Br. J. Nutr. 95(5): 1016-1023.
Dragsted L.O.1998. Natural antioxidants in chemoprevention. Arch. Toxicol Suppl. 20: 209-226.
Du Y., Guo H., Lou H.X. 2007. Grape seed polyphenol protect cardiac cells from apoptosis via induction of endogenous antioxidant enzymes. J. Agric. Food Chem. 55(5): 1695-1701.
Duraj J., Zazrivcova K., Bodo J., et al. 2005. Flavonoid quercetin, but not apigenin or luteolin, induced apoptosis in human myeloid leukemia cells and their resistant variants. Neoplasma. Neoplasma. 52(4): 273-279.
Erhart L.M., Lankat-Buttgereit B., Schmidt H., et al. 2005. Flavone initiates a hierarchical activation of the caspase-cascade in colon cancer cells. Apoptosis. 10(3): 611-617.
Evan G.I., Vousden K.H. 2001. Proliferation, cell cycle and apoptosis in cancer. Nature. 411(6835): 342-348.
Fadeel B., Orrenius S. 2005. Apoptosis: a basic biological phenomenon with wide-ranging implications in human disease. J. Intern. Med. 258(6): 479-517.
Fan T.J., Han L.H., Cong R.S., et al. 2005. Caspase family proteases and apoptosis. Acta. Biochim. Biophys. Sin. (Shanghai). 37(11): 719-727.
Fang J., Xia C, Cao Z., et al. 2005. Apigenin inhibits VEGF and HIF-1 expression via PI3K/AKT/p70S6K1 and HDM2/p53 pathways. FASEB J. 19(3): 342-353.
Fenton J.I., Hord N.G. 2006. Stage matters: choosing relevant model systems to address hypotheses in diet and cancer chemoprevention research. Carcinogenesis. 27(5): 893-902.
Ferguson P.J., Kurowska E., Freeman D.J., et al. 2004. A flavonoid fraction from cranberry extract inhibits proliferation of human tumor cell lines. J. Nutr. 134(6): 1529-1535.
Fink B.N., Steck S.E., Wolff M.S., et al. 2007. Dietary flavonoid intake and breast cancer risk among women on Long Island. Am. J. Epidemiol. 165(5): 514-523
Flores E.R., Tsai K. Y., Crowley D. et al. 2002. p63 and p73 are required for p53-dependent apoptosis in response to DNA damage. Nature. 416(6880): 560-564.
Fotsis T., Pepper M.S., Aktas E., et al. 1997. Flavonoids .dietary derived inhibitors of cell proliferation and in vitro angiogenesis. Cancer Res. 57(14): 2916-2921.
Fridman J.S., Lowe S.W. 2003. Control of apoptosis by p53. Oncogene. 22(56): 9030-9040.
Galati G., Sabzevari O., Wilson J.X., et al. 2002. Prooxidant activity and cellular effects of the phenoxyl radicals of dietary flavonoids and other polyphenolics. Toxicology. 177(1): 91-104.
Garcia-Closas R., Agudo A., Gonzalez C.A., et al. 1998. Intake of specific carotenoids and flavonoids and the risk of lung cancer in women in Barcelona, Spain. Nutr. Cancer. 32(3): 154-158.
Garcia-Closas R., Gonzalez C, Agudo A., et al. 1999. Intake of specific carotenoids and flavonoids and the risk of gastric cancer in Spain. Cancer Causes Control. 10(1): 71-75.
Gates M.A., Tworoger S.S., Hecht J.L., et al. 2007. A prospective analysis of dietary flavonoid intake and epithelial ovarian cancer. Int. J. Cancer. 121(10): 2225-2232.
Graadolatto A., Canivenc-Lavier M.C., Basly J.P., et al. 2004. Metabolism of apigenin by liver phase I and phase II enzymes and by isolated perfused rat liver. Drug Metab. Dispos. 32 (1): 58-65.
Granado-Serrano A.B., Martin M.A., Bravo L., et al. 2006. Quercetin induces apoptosis via caspase activation, regulation of Bcl-2, and inhibition of PI-3-Kinase/Akt and ERK pathways in a human hepatoma cell line (HepG2). J. Nutr. 136(11): 2715-2721.
Granado-Serrano A.B., Martin M.A., Izquierdo-Pulido M., et al. 2007. Molecular mechanisms of (-)-epicatechin and chlorogenic acid on the regulation of the apoptotic and survival/proliferation pathways in a human hepatoma cell line. J. Agric. Food Chem. 55(5): 2020-2027.
Gschwendt M., Horn F., Kittstein W., et al. 1983. Inhibition of the calciumand phospholipid- dependent protein kinase activity from mouse brain cytosol by quercetin. Biochem. Biophys. Res. Commun. 117(2): 444-447.
Guadagno T.M., Newport J.W. 1996. Cdk2 kinase is required for entry into mitosis as a positive regulator of Cdc2-cyclin B kinase activity. Cell. 84(1): 73-82.
Gupta S., Afaq F., Mukhtar H. 2001. Selective growth-Inhibitory, cell cycled deregulatory and apoptotic response of apigenin in normal versus human prostate carcinoma cells. Biochem. Biophys. Res. Commun. 287(4): 914-920.
Gupta S., Afaq F., Mukhtar, H. 2002. Involvement of nuclear factor-kappa B, Bax and Bcl-2 in induction of cell cycle arrest and apoptosis by apigenin in human prostate carcinoma cells. Oncogene. 21(23): 3727-3738.
Guz R.N., Stermitz F.R., Jhonson J.B., et al. 2001. Flavonolignan and flavone inhibitors of a Staphylococcus aureus multidrug resistance pump: structure-activity relationships. J. Med. Chem. 44(2): 261-268.
Haddad A.Q., Venkateswaran V., Viswanathan L, et al 2006. Novel antiproliferative flavonoids induce cell cycle arrest in human prostate cancer cell lines. Prostate Cancer Prostatic Dis. 9(1): 68-76.
Han H.Y., Shan S., Zhang X., et al. 2007. Down-regulation of prostate specific antigen in LNCaP cells by flavonoids from the pollen of Brassica napus L. Phytomedicine. 14(5): 338-43.
Harborne J.B., Williams C.A. 2000. Advances in flavonoid research since 1992. Phytochemistry. 55(6): 481-504.
Hatch F.T., Lightstone F.C., Colvin M.E. 2000. Quantitative structure-activity relationship of flavonoids for inhibition of heterocyclic amine mutagenicity. Environ. Mol. Mutagen. 35(4): 279-299.
Haupt S., Berger M., Goldberg Z., et al. 2003. Apoptosis—the p53 network. J. Cell Sci. 116(pt 20): 4077-4085.
Heber D., Bowerman S. 2001. Applying science to changing dietary patterns. J. Nutr. 131(11 Suppl): 3078S-3081S.
Hecht S.S. 1999. Chemoprevention of cancer by isothiocyanates, modifiers of carcinogen metabolism. J. Nutr. 129(3): 768S-774S.
Hendrich A.B. 2006. Flavonoid-membrane interactions: possible consequences for biological effects of some polyphenolic compounds. Acta Pharmacol. Sin. 27(1): 27-40.
Heo M.Y., Lee S.J., Kwon C.H., et al. 1994. Anticlastogenic effects of galangin against bleomycin-induced chromosomal aberrations in mouse spleen lymphocytes. Mutat. Res. 311(2): 225-229.
Herr I., Debatin K.M. 2001. Cellular stress response and apoptosis in cancer therapy. Blood. 98(9): 2603-2614.
Hirvonen T., Virtamo J., Korhonen P., et al. 2001. Flavonol and flavone intake and the risk of cancer in male smokers (Finland). Cancer Causes Control. 12(9): 789-796.
Hollman P.C., de Vries J.H., van Leeuwen S.D., et al. 1995. Absorption of dietary quercetin glycosides and quercetin in healthy ileostomy volunteers. Am. J. Clin. Nutr. 62(6): 1276-1282.
Hong W.K., Sporn M.B. 1997. Recent advances in chemoprevention of cancer. Science. 278(5340): 1073-1077.
Hooijberg J.H., Broxterman H.J., Heijn M., et al. 1997. Modulation by (iso) flavoniods of the ATPase activity of the multidrug resistance protein. FEBS Lett. 413(2): 344-348.
Horinaka M., Yoshida T., Shiraishi T., et al. 2005. Luteolin induces apoptosis via death receptor 5 upregulation in human malignant tumor cells. Oncogene. 24(48): 7180-7189.
Horinaka M., Yoshida T., Shiraishi T., et al. 2005. The combination of TRAIL and luteolin enhances apoptosis in human cervical cancer HeLa cells. Biochem. Biophys. Res. Commun. 333 (3): 833-838.
Hsiao Y.C., Hsieh Y.S., Kuo W.H., et al. 2007. The tumor-growth inhibitory activity of flavanone and 2'-OH flavanone in vitro and in vivo through induction of cell cycle arrest and suppression of cyclins and CDKs. J. Biomed. Sci. 14(1): 107-119.
Hsu Y.L., Kuo P.L., Liu C.F., et al. 2004. Acacetin-induced cell cycle arrest and apoptosis in human non-small cell lung cancer A549 cells. Cancer Lett. 212(1): 53-60.
Human and Animal Cell Lines (http://www.biotech.ist.unige.it /cldb/cname-1c.html) Imai Y., Tsukahara S., Asada S., et al. 2004. Phytoestrogens/flavonoids reverse breast cancer resistance protein/ABCG2-mediated multidrug resistance. Cancer Res. 64(12): 4346-4352.
Innocente S.A., Lee J.M. 2005. p73 is a p53-independent, Sp1-dependent repressor of cyclin B1 transcription. Biochem. Biophys. Res. Commun. 329 (2): 713-718.
Ismail I.A., Kang K.S., Lee H.A., et al. 2007. Genistein-induced neuronal apoptosis and G2/M cell cycle arrest is associated with MDC1 up-regulation and PLK1 down-regulation. Eur. J. Pharmacol. 575(1-3): 12-20.
Jeffrey P.D., Russo A.A., Polyak K., et al. 1995. Mechanism of CDK activation related by the structure of cyclin A-cdk2 complex. Nature. 376(6538): 313-320.
Jin S., Antinore M.J, Lung F.D., et al. 2000. The GADD45 inhibition of Cdc2 kinase correlates with GADD45-mediated growth suppression. J. Biol. Chem. 275(22): 16602-16608.
Kal H.B., de Graaff E., Van Berkel A.H., et al. 1992. Responses of experimental rat tumours and a mouse colon tumour to flavone acetic acid. In Vivo. 6(1): 73-75.
Kanakis C.D., Tarantilis P.A., Polissiou M.G, et al. 2007. An overview of DNA and RNA bindings to antioxidant flavonoids. Cell Biochem. Biophys. 49(1): 29-36.
Kandaswami C, Perkins E., Soloniuk D.S., et al. 1991. Antiproliferative effects of citrus flavonoids on a human squamous cell carcinoma in vitro. Cancer Lett. 56 (2): 147-152.
Kawaii S., Tomono Y., Katase E., et al. 1999. Effect of citrus flavonoids on HL-60 cell differentiation. Anticancer Res. 19(2A): 1261-1269.
Khan T.H., Sultana S. 2006: Apigenin induces apoptosis in Hep G2 cells: Possible role of TNF-a and IFN-γ. Toxicology 217 (2-3): 206-212.
Kim D.H., Kim S.Y., Park S.Y., et al. 1999. Metabolism of quercitrin by human intestinal bacteria and its relation to some biological activities. Biol. Pharm. Bull. 22 (7): 749-751.
Kim M.J., Kim Y.J., Park H.J., et al. 2006. Apoptotic effect of red wine polyphenol on human colon cancer SNU-C4 cells. Food Chem. Toxicol. 44 (6): 898-902.
Kitagawa S. 2006. Inhibitory Effects of polyphenol on P-glycoprotein-mediated transport. Biol. Pharm. Bull. 29(1): 1-6.
Knekt P., Jarvinen R., Seppanen R., et al. 1997. Dietary flavonoids and the risk of lung cancer and other malignant neoplasms. Am. J. Epidemiol. 146(3): 223-230.
Knekt P., Kumpulainen J., Jarvinen R., et al. 2002. Flavonoid intake and risk of chronic diseases. Am. J. Clin. Nutr. 76(3): 560-568.
Knowles L.M., Zigrossi D.A., Tauber R.A., et al. 2000. Flavonoids suppress androgen-independent human prostate tumor proliferation. Nutr. Cancer. 38(1): 116-122.
Ko C.H., Shen S.C., Chen Y.C. 2004. Hydroxylation at C4V or C6 is essential for apoptosis- inducing activity of flavanones through activation of caspase-3 cascade and production of reactive oxygen species. Free Radical Biol. Med. 36(7): 897-910.
Ko C.H., Shen S.C., Lee T.J.F., et al. 2005. Myricetin inhibits matrix metalloproteinase- protein expression and enzyme activity in colorectal carcinoma cells. Mol. Cancer Ther. 4(2): 281-290.
Kobayakawa J., Sato Nishimori F., Moriyasu M., et al. 2004. G2-M arrest and antimitotic activity mediated by casticin, a flavonoid isolated from Viticis Fructus (Vitex rotundifolia Linne fil.) Cancer Lett. 208(1): 59-64.
Kobayashi T., Nakata T., Kuzumaki T. 2002. Effect of flavonoids on cell cycle progression in prostate cancer cells. Cancer Lett. 176(1): 17-23.
Kuntz S., Wenzel U., Daniel H. 1999. Comparative analysis of the effects of flavonoids on proliferation, cytotoxicity, and apoptosis in human colon cancer cell lines. Eur. J. Nutr. 38(3):133-142.
Kuo H.M., Chang L.S., Lin Y.L., et al. 2007. Morin inhibits the growth of human leukemia HL-60 cells via cell cycle arrest and induction of apoptosis through mitochondria dependent pathway. Anticancer Res. 27(1A): 395- 405.
Kuo S.M. 1996. Antiproliferative potency of structurally distinct dietary flavonoids on human colon cancer cells. Cancer Lett. 110(1-2): 41-48.
Lagergren L. 2005. Adenocarcinoma of oesophagus: what exactly is the size of the problem and who is at risk? Gut. 54(Suppl 1): il-i5.
Lam A.K.Y. 2000. Molecular biology of esophageal squamous cell carcinoma. Critical Reviews in Oncology/Hematology. 33(2): 71-90.
Layke J.C., Lopez P.P. 2006. Esophageal Cancer: A Review and Update. Am. Fam. Physician. 73: 2187-2194.
Lazze M.C., Savio M., Pizzala R., et al. 2004. Anthocyanins induce cell cycle perturbations and apoptosis in different human cell lines. Carcinogenesis. 25(8): 1427-1433.
Le Marchand L., Murphy S., Hankin J., et al. 2000. Intake of flavonoids and lung cancer. J. Natl. Cancer Inst. 92(2): 154-160.
Lee H.J., Wang C.J., Kuo H.C., et al. 2005. Induction apoptosis of luteolin in human hepatoma HepG2 cells involving mitochondria translocation of Bax/Bak and activation of JNK. Toxicology and Applied Pharmacology. 203(2): 124-131.
Lehrbach D.M., Nita M.E., Cecconello I. 2003. Molecular aspects of esophageal squamous cell carcinoma carcinogenesis. Clinical Genomics of Esophageal Cancer Group. 40(4): 256-261.
Leung H.W.C., Lin C.J., Hour M.J., et al. 2007. Kaempferol induces apoptosis in human lung non-small carcinoma cells accompanied by an induction of antioxidant enzymes. Food and Chemical Toxicology. 45(10): 2005-2013.
Leung H.W.C., Yang W.H., Lai M.Y., et al. 2007. Inhibition of 12-lipoxygenase during baicalein-induced human lung nonsmall carcinoma H460 cell apoptosis. Food and Chemical Toxicology. 45(3): 403-411.
Lim do Y, Jeong Y, Tyner A.L., et al. 2007. Induction of cell cycle arrest and apoptosis in HT-29 human colon cancer cells by the dietary compound luteolin. Am. J. Physiol. Gastrointest. 292(1): G66-75.
Lin J., Zhang S.M., Wu K. 2006. Flavonoid intake and colorectal cancer risk in men and women. Am. J. Epidemiol. 164(7): 644-651.
Lin Y.T., Hsiu S.L., Hou Y.C., et al. 2003. Degradation of flavonoid aglycones by rabbit, rat and human fecal flora. Biol. Pharm. Bull. 26(5): 747-751.
Lindenmeyer F., Li H., Menashi S., et al. 2001. Apigenin acts on the tumor cell invasion process and regulates protease production. Nutr. Cancer. 39(1): 139-147.
Liu L.Z., Fang J., Zhou Q., et al. 2005. Apigenin inhibits expression of vascular endothelial growth factor and angiogenesis in human lung cancer cells: implication of chemoprevention of lung cancer. Mol. Pharmacol. 68(10): 635-643.
Liu R.H. 2004. Potential synergy of phytochemicals in cancer prevention: mechanism of action. J. Nutr. 134(12 Suppl): 3479S-3485S.
Liu T., Xu Z. M., He Q. J., et al. 2007. Nitrogen-containing flavonoids as CDK1/Cyclin B inhibitors: Design, synthesis, and biological evaluation. Bioorganic & Medicinal Chemistry Letters. 17(1): 278-281.
Lopez-Lazaro M. 2002. Flavonoids as anticancer agents: structure-activity relationship study. Curr. Med. Chem. Anticancer Agents. 2(6): 691-714.
Lu X., Jung J., Cho H.J., et al. 2005. Fisetin inhibits the activities of cyclin-dependent kinases leading to cell cycle arrest in HT-29 human colon cancer cells. J. Nutr. 135(12): 2884-2890.
Luk S.C., Siu S.W., Lai C.K., et al. 2005. Cell cycle arrest by a natural product via G2/M checkpoint. Int. J. Med. Sci. 2(2): 64-69.
Mak P., Leung Y.K., Tang W.Y., et al. 2006. Apigenin suppresses cancer cell growth through ERβ. Neoplasia. 8(11): 896-904.
Makita H., Tanaka T., Fujitsuka H., et al. 1996. Chemoprevention of 4-nitraquinoline 1-oxide-induced rat oral carcinogenesis by the dietary flavonoids chalcone, 2-hydroxychalcone, and quercetin. Cancer Res. 56: 4904-4909.
Manach C., Morand C., Crespy V., et al. 1998. Quercetin is recovered in human plasma as conjugated derivatives which retain antioxidant properties. FEBS Lett. 426(3): 331-336.
Manach C., Morand C., Texier O., et al. 1997. Bioavailability of rutin and quercetin in rats. FEBS Lett. 409(1): 12-16.
Manach C., Scalbert A., Morand C., et al. 2004. Polyphenols: food sources and bioavailability. Am. J. Clin. Nutr. 79(5): 727-747.
Manthey JA, Guthrie N. 2002. Antiproliferative activities of citrus flavonoids against six human cancer cell lines. J. Agric. Food Chem. 50(21): 5837-5843.
Marchenko N.D., Zaika A., Moll U.M. 2000. Death signal-induced localization of p53 protein to mitochondria. A potential role in apoptotic signaling. J. Biol. Chem. 275(21): 16202-16212.
Martens S., Mithofer A. 2005. Flavones and flavone synthases. Phytochemistry. 66(20): 2399-2407.
Martin K.R. 2006. Targeting apoptosis with dietary bioactive agents. Exp. Biol. Med. 231(2): 117-129.
Matsui J., Kiyokawa N., Takenouchi H., et al. 2005. Dietary bioflavonoids induce apoptosis in human leukemia cells. Leuk. Res. 29(5): 573-581
Mayne S.T., Risch H.A., Dubrow R., et al. 2001. Nutrient intake and risk of subtypes of esophageal and gastric cancer. Cancer Epidemiol Biomarkers Prev. 10(10): 1055-1062
McCabe M.L., Dlamini Z. 2005. The molecular mechanisms of oesophageal cancer. Int. Immunopharmacol. 5(7-8): 1113-1130
Melino G., Bernassola F., Ranalli M., et al. 2004. p73 Induces apoptosis via PUMA transactivation and Bax mitochondrial translocation. J. Biol. Chem. 279(9): 8076-8083.
Middleton E., Kandaswami C, Theoharides T.C. 2000. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev. 52(4): 673-751.
Min K., Ebeler S.E. 2008. Flavonoid effects on DNA oxidation at low concentrations relevant to physiological levels. Food Chem. Toxicol. 46(1): 96-104
Miocinovic R., McCabe N.P., Keck R.W., et al. 2005. In vivo and in vitro effect of baicalein on human prostate cancer cells. Int. J. Oncol. 26 (1): 241-246.
Moll U.M., Slade N. 2004. p63 and p73 roles in development and tumor formation. Mol. Cancer Res. 2(7): 371-386.
Moore J.D., Yang J., Truant R., et al. 1999. Nuclear import of Cdk/cyclin complexes: identification of distinct mechanisms for import of Cdk2/cyclin E and Cdc2/cyclin B1. J. Cell Biol. 144(2): 213-224
Morand C, Manach C, Crespy V., et al. 2000. Quercetin 3-O-β-glucoside is better absorbed than other quercetin forms and is not present in rat plasma. Free Rad. Res. 33(5): 667-676.
Morley K.L., Ferguson P.J., Koropatnick J. 2007. Tangeretin and nobiletin induce G1 cell cycle arrest but not apoptosis in human breast and colon cancer cells. Cancer Lett. 251(1): 168-178.
Mu C., Jia P., Yan Z., et al. 2007. Quercetin induces cell cycle G1 arrest through elevating Cdk inhibitors p21 and p27 in human hepatoma cell line (HepG2). Methods Find Exp. Clin. Pharmacol. 29(3): 179-183
Murray T.J., Yang X.h., Sherr D.H. 2006. Growth of a human mammary tumor cell line is blocked by galangin, a naturally occurring bioflavonoid, and is accompanied by down-regulation of cyclins D3, E, and A. Breast Cancer Res. 8(2): R17
Mutoh M., Takahashi M., Fukuda K., et al. 2000. Suppression by flavonoids of cyclooxygenase-2 promoter-dependent transcriptional activity in colon cancer cells: structure-activity relationship. Jpn. J. Cancer Res. 91(7): 686-91.
Naik, H.R., Lehr, et al. 1994. An in vitro and in vivo study of antitumor effects of genistein on hormone refractory prostate cancer. Anticancer Res. 14(6B): 2617-2620.
Nair H.K., Rao K.V.K., Aalinkeel R., et al. 2004. Inhibition of prostate cancer cell colony formation by the flavonoid quercetin correlates with modulation of specific regulatory genes. Clin. Diagn. Lab. Immunol.. 11(1): 63-69
Nakadate T., Yamamoto S., Aizu E., et al. 1983. Effects of flavonoids and antioxidants on 12-O-tetradecanoyl-phorbol-13-acetate-caused epidermal ornithinedecarboxylase induction and tumor promotion in relation to lipoxygenase inhibition by these compounds. Gann. 75(3): 214-222.
Neuhouser M.L. 2004. Dietary flavonoids and cancer risk: evidence from human population studies. Nutr. Cancer. 50(1): 1-7.
Nguyen T.T., Tran E., Nguyen T., et al. 2004. The role of activated MEK-ERK pathway in quercetin-induced growth inhibition and apoptosis in A549 lung cancer cells. Carcinogenesis. 25(5): 647-659.
Nguyen T.T., Tran E., Ong C.K., et al. 2003. Kaempferol-Induced Growth Inhibition and Apoptosis in A549 Lung Cancer Cells Is Mediated by Activation of MEK-MAPK. J. Cell. Physiol. 197(1): 110-121.
Nielsen S.E., Breinholtv., Justesen U., et al. 1998. In vitro biotransfoumation of flavonoids by rat liver microsomes. Xenobiotica. 28(4): 389-401.
Nishino H., Nagao M., Fujiki H., et al. 1983. Role of flavonoids in suppressingthe enhancement of phospholipid metabolism by tumor promoters. Cancer Lett. 21(1): 1-8.
Nishino H., Naito E., Iwashima A., et al. 1984. Interaction between quercetin and Ca~(2+) calmodulin complex: Possible mechanism for anti-tumor-promoting action of the flavonoids. Gann. 75(4): 311-316.
Norman H. A., Go V. L., Butrum R.R. 2004. Review of the international research conference on food, nutrition, and cancer, 2004. J. Nutr. 134(12 Suppl): 3391S-3393S.
Nothlings U., Murphy S.P., Wilkens L.R., et al. 2007. Flavonols and pancreatic cancer risk: the multiethnic cohort study. Am. J. Epidemiol. 166(8): 924-931.
O'Leary K.A., Day A.J., Needs P.W., et al. 2001. Flavonoid glucuronides are substrates for human liver beta -glucuronidase. FEBS Lett. 503(1): 103-106.
O'Leary K.A., de Pascual-Tereasa S., Needs P.W., et al. 2004. Effect of flavonoids and Vitamin E on cyclooxygenase-2 (COX-2) transcription. Mutat .Res. 551 (1-2): 245-254.
Oh S.M., Chung K.H. 2004. Estrogenic activities of Ginkgo biloba extracts. Life Sci. 74(11): 1325-1335.
Oki T., Sowa Y., Hirose T., et al. 2004. Genistein induces Gadd45 gene and G2/M cell cycle arrest in the DU145 human prostate cancer cell line. FEBS Lett. 577(1-2): 55-59.
Olthof M.R., Hollman P.C., Vree T.B., et al. 2000. Bioavailabilities of quercetin-3-glucoside and quercetin-4'-glucoside do not differ in humans. J. Nutr. 130(5): 1200-1203.
Ong C.S., Tran E., Nguyen T.T., et al. 2004. Quercetin-induced growth inhibition and cell death in nasopharyngeal carcinoma cells are associated with increase in Bad and hypophosphorylated retinoblastoma expressions. Oncol. Rep. 11(3): 727-733.
Oniscu A., Sphyris N., Morris R.G., et al. 2004. p73a is a candidate effector in the p53 independent apoptosis pathway of cisplatin damaged primary murine colonocytes. J. Clin. Pathol. 57(5): 492-498.
Otake Y., Hsieh F., Walk T. 2002. Glucuronidation versus oxidation of the flavonoid galangin by human liver microsomes and heptocytes. Drug Metab. Dispos. 30(5): 576-581.
Pan M.H., Chen W.J., Lin-Shiau S.Y., et al. 2002. Tangeretin induces cell-cycle G1 arrest through inhibiting cyclin-dependent kinases 2 and 4 activities as well as elevating Cdk inhibitors p21 and p27 in human colorectal carcinoma cells. Carcinogenesis. 23(10): 1677-1684.
Parmar V.S., Jain R., Sharma S.K., et al. 1994. Anti-invasive activity of 3,7-dimethoxyflavone in vitro. J. Pharm. Sci. 83(9): 1217-1221.
Passamonti S., Vrhovsek U., Vanzo A., et al. 2003. The stomach as a site for anthocyanins absorption from food. FEBS Lett. 544(1-3): 210-213.
Peterson J., Lagiou P., Samoli E., et al. 2003. Flavonoid intake and breast cancer risk: a case-control study in Greece. Br. J. Cancer. 89(7): 1255-1259.
Pouget C, Lauthier E, Simon A., et al. 2001. Flavonoids: structural requirements for antiproliferative activity on breast cancer cells. Bioorg. Med. Chem. Lett. 11(24): 3095-3097.
Pucci B., Kasten M., Giordano A., 2000. Cell cycle and apoptosis. Neoplasia. 2(4): 291-299.
Ramos S. 2007. Effects of dietary flavonoids on apoptotic pathways related to cancer chemoprevention. J. Nutr. Biochem. 18(7): 427-442.
Ramos S., Alia M., Bravo L., et al. 2005. Comparative effects of food-derived polyphenol on the viability and apoptosis of a human hepatoma cell line (HepG2). J. Agric. Food Chem. 53(4): 1271-1280.
Redrejo-Rodriguez M., Tejeda-Cano A., Pinto M.C., et al. 2004. Lipoxygenase inhibition by flavonoids: semiempirical study of the structure-activity relation. Journal of Molecular Structure (Theochem). 674 (1-3);. 121-124.
Reed J.C. 2000. Mechanisms of Apoptosis. Am. J. Pathol. 157(5): 1415-1430.
Ren W., Qiao Z., Wang H., et al. 2003. Flavonoids: promising anticancer agents. Med. Res. Rev. 23(4): 519-534.
Rosenkranz H.S., Thampatty B.P. 2003. SAR: flavonoids and COX-2 inhibition. Oncol Res. 13(12): 529-535.
Rossi M., Garavello W., Talamini R., et al. 2007. Flavonoids and the risk of oral and pharyngeal cancer: a case-control study from Italy. Cancer Epidemiol. Biomarkers. Prev. 16(8): 1621-1625.
Rossi M., Negri E., Talamini R., et al. 2006. Flavonoids and colorectal cancer in Italy. Cancer Epidemiol. Biomarkers Prev. 15(8): 1555-1558.
Rusak G., Gutzeit H., Muller J. 2005. Structurally related flavonoids with antioxidative properties differentially affect cell cycle progression and apoptosis of human acute leukemia cells. Nutrition Research. 25(2): 143-155.
Russo G. L. 2007. Ins and outs of dietary phytochemicals in cancer chemoprevention. Biochem. Pharmacol. 74(4): 533-544.
Russo M., Palumbo R., Tedesco 1., et al. 1999. Quercetin and anti-CD95 (Fas/Apol) enhance apoptosis in HPB-ALL cell line. FEBS. 462(3): 322-328.
Sagar S.M., Yance D., Wong R.K. 2006. Natural health products that inhibit angiogenesis: a potential source for investigational new agents to treat cancer-part 2. Curr. Oncol.l3(3): 99-107.
Salucci M., Stivala L.A., Maiani G., et al. 2002. Flavonoids uptake and their effect on cell cycle of human colon adenocarcinoma cells (Caco2). Br. J. Cancer. 86 (10): 1645-1651.
Sasaki M., Nakamura H., Tsuchiya S., et al. 2007. Quercetin-induced PC12 cell death accompanied by caspase-mediated DNA fragmentation. Biol. Pharm. Bull. 30(4): 682-686.
Scambia G., Ranelletti F.O., Panici P.B., et al. 1994. Quercetin potentiates the effect of adriamycin in a multidnig-resistant MCF-7 human breast-cancer cell line: P-glycoprotein as a possible target. Cancer Chemother. Pharmacol. 34 (6): 459-464.
Schneider H., Blaut M. 2000. Anaerobic degradation of flavonoids by eubacterium ramulus. Arch. Microbiol. 173(1): 71-75.
Schoefer L., Mohan R., Schwiertza., et al. 2003. Anaerobic degradation of flavonoids by clostridium orbiscindens. Appl Environ Microbiol. 69(10): 5849-5854.
Schwartz G.K., Shah M.A. 2005. Targeting the Cell Cycle: A New Approach to Cancer Therapy. J .Clin.Oncol. 23(36): 9408-9421.
Senderowicz A. M. 1999. Flavopiridol: the first cyclin-dependent kinase inhibitor in human clinical trials. Invest New Drugs. 17(3): 313-320.
Shapiro G. I., Koestner D.A., Matranga C. B., et al. 1999. Flavopiridol induces cell cycle arrest and p53-independent apoptosis in non-small cell lung cancer cell lines. Clin.Cancer Res. 5(10): 2925-2938.
Sharma Y., Agarwal C, Singh A.K., et al. 2001. Inhibitory effect of silibinin on ligand binding to erbB1 and associated mitogenic signaling, growth, and DNA synthesis in advanced human prostate carcinoma cells. Mol. Carcinog. 30(4): 224-236.
Shen S.C., Ko C.H., Tseng S.W., et al. 2004. Structurally related antitumor effects of flavanones in vitro and in vivo: involvement of caspase 3 activation, p21 gene expression, and reactive oxygen species production. Toxicol. Appl. Pharmacol. 197(2): 84-95.
Shon Y.H., Park S.D., Nam K.S. 2006. Effective chemopreventive activity of genistein against human breast cancer cells. J. Biochem. Mol. Biol. Jul. 39(4): 448-451.
Shukla S. Gupta S. 2004. Molecular mechanisms for apigenin-induced cell-cycle arrest and apoptosis of hormone refractory human prostate carcinoma DU145 cells. Mol. Carcinog. 39(2): 114-126.
Shukla S., Gupta S. 2006. Molecular targets for apigenin-induced cell cycle arrest and apoptosis in prostate cancer cell xenograft. Mol. Cancer Ther. 5(4): 843 - 852.
Shukla S., Gupta S. 2007. Apigenin-induced cell cycle arrest is mediated by modulation of MAPK, PI3K-Akt, and loss of Cyclin D1 associated retinoblastoma dephosphorylation in human prostate cancer cells. Cell Cycle. 6(9): 1102-1114.
Singh R.P., Agarwal R. 2006. Natural flavonoids targeting deregulated cell cycle progression in cancer cells. Curr. Drug Targets. 7(3): 345-354.
Singh R.P., Agrawal P., Yim D., et al. 2005. Acacetin inhibits cell growth and cell cycle progression, and induces apoptosis in human prostate cancer cells: structure-activity relationship with linarin and linarin acetate. Carcinogenesis. 26(4): 845-854.
Singh R.P., Dhanalakshmi S., Agarwal R. 2002. Phytochemicals as cell cycle modulators—a less toxic approach in halting human cancers. Cell Cycle. 1(3): 156-161.
Smits V.A., Klompmaker R., Vallenius T., et al. 2000. p21 inhibits Thrl61 phosphorylation of Cdc2 to enforce the G2 DNA damage checkpoint. J. Biol. Chem. 275(39): 30638-30643.
Spencer J.P., Abd-el-Mohsen M.M., Rice-Evans C. 2004. Cellular uptake and metabolism of flavonoids and their metabolites: implications for their bioactivity. Arch. Biochem. Biophys. 423(1): 148-161.
Stark G.R., Taylor W.R. 2004. Analyzing the G2/M checkpoint. Methods Mol. Biol. 280: 51-82.
Stefani E.D., Boffetta P., Deneo-Pellegrini H., et al. 1999. Dietary antioxidants and lung cancer risk: a case-control study in Uruguay. Nutr. Cancer. 34(1): 100-110.
Steinmetz K.A., Potter J.D. 1996. Vegetables, fruit, and cancer prevention: a review. J. Am. Diet Assoc. 96(10): 1027-1039.
Stiewe T., Putzer B. M. 2001. p73 in apoptosis. Apoptosis. 6(6): 447-452.
Stiewe T., Putzer B. M. 2002. Role of p73 in malignancy: tumor suppressor or oncogene? Cell Death Differ. 9(3): 237-245.
Surh Y.J., 2003. Cancer chemoprevention with dietary phytochemicals.Nat. Rev. cancer. 3(10): 768-780.
Takagaki N., Sowa Y., Oki T., et al. 2005. Apigenin induces cell cycle arrest and p21/WAF1 expression in a p53-independent pathway. Int. J. Oncol. 26(1): 185-189.
Takahashi T., Kobori M., Shinmoto H., et al..1998. Structure-activity relationships of flavonoids and the induction of granulocytic- or monocytic-differentiation in HL60 human myeloid leukemia cells. Biosci.. Biotechnol. Biochem. 62(11): 2199-2204.
Takizawa C.G., Weis K, Morgan D.O., 1999. Ran-independent nuclear import of cyclin B1-Cdc2 by importin beta. Proc. Natl. Acad. Sci. USA. 96(14): 7938-7943.
Tanaka T., Makita H., Ohnishi M., et al. 1997. Chemoprevention of 4-nitroquinoline-1-oxide-induced oral carcinogenesis in rats by flavonoids diosmin and hesperidin, each alone and in combination. Cancer Res. 57(2): 246-252.
Tatsuta A., Iishi H., Baba M., et al. 2000. Suppression by apigenin of peritoneal metastasis of intestinal adenocarcinomas induced by azoxymethane in Wistar rats. Clin. Exp. Metastasis. 18(8): 657-662.
Taylor W.R., Stark G.R. 2001. Regulation of the G2/M transition by p53. Oncogene. 20(15): 1803-1815.
Theodoratou E., Kyle J.,. Cetnarskyj R., et al. 2007. Dietary flavonoids and the risk of colorectal cancer. Cancer Epidemiol. Biomarkers Prev. 16(4): 684-693.
Torkin R., Lavoie J.F., Kaplan D.R., et al. 2005. Induction of caspase-dependent, p53-mediated apoptosis by apigenin in human neuroblastoma. Mol. Cancer Ther. 4(1): 1-11.
Tyagi A., Agarwal C, Harrison G., et al. 2004. Silibinin causes cell cycle arrest and apoptosis in human bladder transitional cell carcinoma cells by regulating CDKI-CDK-cyclin cascade, and caspase 3 and PARP cleavages. Carcinogenesis. 25(9): 1711-1720.
Tyagi A., Bhatia N., Condon M.S., et al. 2002. Antiproliferative and apoptotic effects of silibinin in rat prostate cancer cells. Prostate. 53(3): 211-217.
Ujiki M.B., Ding X.Z., Salabat M.R., et al. 2006. Apigenin inhibits pancreatic cancer cell proliferation through G2/M cell cycle arrest. Mol. Cancer. 76 (5): 1-8.
Varghese L., Agarwal G.Tyagi A., et al. 2005. Silibinin efficacy against human hepatocellular carcinoma. Clin. Cancer Res. 11(23): 8441-8448.
Vargo M.A., Voss O.H., Poustka F., et al. 2006. Apigenin-induced-apoptosis is mediated by the activation of PKCd and caspases in leukemia cells. Biochem. Pharmacol. 72(6): 681-692.
Vauzour D., Vafeiadou K., Rice-Evans C., et al. 2007. Inhibition of cellular proliferation by the genistein metabolite 5,7,3',4'-tetrahydroxyisoflavone is mediated by DNA damage and activation of the ATR signalling pathway. Arch. Biochem. Biophys. 468(2): 159-166.
Veeriah S., Kautenburger T., Habermann N., et al. 2006. Apple flavonoids inhibit growth of HT29 human colon cancer cells and modulate expression of genes involved in the biotransformation of xenobiotics. Mol. Carcinog. 45(3): 164-174.
Versantvoort C.H., Rhodes T., Twentyman P.R. 1996. Acceleration of MRP-associated efflux of rhodamine 123 by genistein and related compounds. Br. J. Cancer. 74(12): 1949-1954.
Vidal A., Koff A. 2000. Cell-cycle inhibitors: three families united by a common cause. Gene. 247(1-2): 1-15.
Vijayababu M., Kanagaraj P., Arunkumar A., et al. 2005. Quercetin-induced growth inhibition and cell death in prostatic carcinoma cells (PC-3) are associated with increase in p21 and hypophosphorylated retinoblastoma proteins expression. J. Cancer Res. Clin. Oncol. 131(11): 765-771.
Virgili F., Acconcia F., Ambra R., et al. 2004. Nutritional flavonoids modulate estrogen receptor alpha signaling. IUBMB Life. 56(3): 145-151.
Vousden K.H. 2006. Outcomes of p53 activation-spoilt for choice. J. Cell Sci.119 (24): 5015-5020.
Walgren R.A., Lin J.T., Kinne R.K., et al. 2000. Cellular uptake of dietary flavonoid quercetin 4'-beta-glucoside by sodium-dependent glucose transporter SGLT1. J Pharmacol. Exp. Ther. 294 (3): 837-843.
Walgrenra R.A., Karnaky K.J.Jr., Lindenmayer G.E., et al. 2000. Efflux of dietary flavonoid quercetin-4'-beta-glucoside across human intestinal Caco-2 cell monolayers by apical multidrug resistance-associated protein-2. J. Pharmacol. Exp.Ther. 294(3): 830-836.
Walle T. 2004. Absorption and metabolism of flavonoids. Free Radic. Biol. Med. 36(7): 829-837.
Walle T. 2007. Methoxylated flavones, a superior cancer chemopreventive flavonoid subclass? Semin. Cancer Biol. 17(5): 354-362.
Walle T., Otake Y., Walle U. K., et al. 2000. Quercetin glucosides are completely hydrolyzed in ileostomy patients before absorption. J. Nutr. 130(11): 2658-2661.
Wang I.K., Lin-Shiau S.Y., Lin J.K., 1999. Induction of apoptosis by apigenin and related flavonoids through cytochrome c release and activation of caspase-9 and caspase-3 in leukaemia HL-60 cells. Eur. J. Cancer. 35(10): 1517-1525.
Wang W., VanAlstyne P.C., Irons K.A., et al. 2004. Individual and interactive effects of apigenin analogs on G2/M cell-cycle arrest in human colon carcinoma cell lines. Nutr. Cancer. 48(1): 106-114.
Wargovich M.J., Eng V.W., Newmark H.L. 1985. Inhibition by plant phenols of benzo[a]pyrene- induced nuclear aberrations in mammalian intestinal cells: A rapid in vivo assessment method. Food Chem. Toxicol. 23(1): 47-49.
Wartenberg M., Budde P., De Marees M., et al. 2003. Inhibition of tumor-induced angiogenesis and matrix-metalloproteinase expression in confrontation cultures of embryoid bodies and tumor spheroids by plant ingredients used in traditional Chinese medicine. Lab. Invest. 83 (1): 87-98.
Watanabe C.M., Wolffram S., Ader P., et al. 2001. The in vivo neuromodulatory effects of the herbal medicine ginkgo biloba. Proc. Natl. Acad. Sci.USA. 98 (12): 6577-6580.
Way T.D., Kao M.C., Lin J.K. 2004. Apigenin induces apoptosis through proteasomal degradation of HER2/neu in HER2/neu-overexpressing breast cancer cells via the Phosphatidylinositol 3-Kinase/Akt-dependent pathway. J. Biol. Chem. 279(6): 4479-4489.
WCRF/AICR: Food, nutrition and the prevention of cancer: a global perspective: World Cancer Research Fund /American Institute for Cancer Research 1997.
Wen X., Walle T. 2006. Methylated Flavonoids have greatly improved intestinal absorption and metabolic stability. Drug Metab. Dispos. 34(10): 1786-1792.
Weng M.S., Ho Y.S., Lin J.K. 2005. Chrysin induces G1 phase cell cycle arrest in C6 glioma cells through inducing p21Wafl/Cipl expression: involvement of p38 mitogen-activated protein kinase. Biochem. Pharmacol. 69 (12): 1815-1827.
Wenzel U., Kuntz S., Brendel M.D., et al. 2000. Dietary flavone is a potent apoptosis inducer in human colon carcinoma cells. Cancer Res. 60(14): 3823-3831.
Wenzel U., Nickel A., Daniel H. 2005. Increased mitochondrial palmitoylcarnitine/ carnitine countertransport by flavone causes oxidative stress and apoptosis in colon cancer cells. Cell Mol. Life Sci. 62(24): 3100-3105.
Westfall M.D., Pietenpol J.A. 2004. p63: molecular complexity in development and cancer. Carcinogenesis. 25(6): 857-864.
Willett W. C. 2000. Diet and cancer. Oncologist. 5(5): 393-404.
Wolffram S., Block M., Ader P. 2002. Quercetin-3-glucoside is transported by the glucose carrier SGLT1 across the brush border membrane of rat small intestine. J. Nutr. 132(4): 630-635.
Woo K.J., Jeong Y.J., Park J.W., et al. 2004. Chrysin-induced apoptosis is mediated through caspase activation and Akt inactivation in U937 leukemia cells. Biochem. Biophys. Res. Commun. 325 (4): 1215-1222.
Yanez J., Vicente V, Alcaraz M., et al. 2004. Cytotoxicity and antiproliferative activities of several phenolic compounds against three melanocytes cell lines: relationship between structure and activity. Nutr. Cancer. 49(2): 191-199.
Yang J.H., Hsia T.C., Kuo H.M., et al. 2006. Inhibition of lung cancer cell growth by quercetin glucuronides via G2/M arrest and induction of apoptosis. Drug Metab. Dispos. 34(2): 296-304.
Yi W., Fischer J., Krewer G., et al. 2005. Phenolic compounds from blueberries can inhibit colon cancer cell proliferation and induce apoptosis. J. Agric. Food Chem. 53(18): 7320-7329.
Yin F., Giuliano A.E., Law R.E., et al. 2001. Apigenin inhibits growth and induces G2/M arrest by modulating cyclin-CDK regulators and ERK/MAP kinase activation in breast carcinoma cells. Anticancer Res. 21(1A): 413-420.
Yoshida T., Maeda A., Horinaka M., et al. 2005. Quercetin induces gadd45 expression through a p53-independent pathway. Oncol. Rep. 14(5): 1299-1303.
Yoshimizu N., Otani Y., Saikawa Y., et al. 2004. Anti-tumour effects of nobiletin, a citrus flavonoid, on gastric cancer include: antiproliferative effects, induction of apoptosis and cell cycle deregulation. Aliment Pharmacol. Ther. 20(Suppl 1): 95-101.
Zava D.T., Duwe G 1997. Estrogenic and antiproliferative properties of genistein and other flavonoids in human breast cancer cells in vitro. Nutr. Cancer. 27(1): 31-40.
Zhan Q., Antinore M.J:, Wang X.W., et al. 1999. Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45. Oncogene. 18(18): 2892-2900.
Zhang H., Chen S.H., Li Y.M. 2004. Epidemiological investigation of esophageal carcinoma. World J. Gastroenterol. 10(12): 1834-1835.
Zhang Q., Zhao X.H., Wang Z.J. 2008. Flavones and flavonols exert cytotoxic effects on a human oesophageal adenocarcinoma cell line (OE33) by causing G2/M arrest and inducing apoptosis. Food Chem Toxicol. 46(6): 2042-2053
Zhang S., Yang X., Morris M.E. 2004. Flavonoids Are Inhibitors of Breast Cancer Resistance Protein (ABCG2)-Mediated Transport. Mol. Pharmacol. 65(5): 1208-1216.
Zhang T., Chen X., Qu L, et al. 2004. Chrysin and its phosphate ester inhibit cell proliferation and induce apoptosis in Hela cells. Bioorg. Med. Chem.12 (23): 6097-6105.
Zhang X.M., Chen J., Xia Y.G., et al 2005. Apoptosis of murine melanoma B16-BL6 cells induced by quercetin targeting mitochondria, inhibiting expression of PKC-alfa and translocating PKC-delta. Cancer Chemother. Pharmacol. 55(3): 251-262.
Zhang Y., Talalay P. 1994. Anticarcinogenic activities of organic isothiocyanates: chemistry and mechanisms. Cancer Res. 54(7 Suppl): 1976s-1981s.
Zheng P.W., Chiang L.C., Lin C.C. 2005. Apigenin induced apoptosis through p53-dependent pathway in human cervical carcinoma cells. Life Sci. 76 (12): 1367-1379.
Zi X., Agarwal R. 1999. Silibinin decreases prostate-specific antigen with cell growth inhibition via G1 arrest, leading to differentiation of prostate carcinoma cells: implications for prostate cancer intervention. Proc. Natl. Acad. Sci. USA. 96(13): 7490-7595.
Zi X., Grasso A.W., Kung H.J., et al. 1998. A flavonoid antioxidant, silymarin, inhibits activation of erbB1 signaling and induces cyclin-dependent kinase inhibitors, Gl arrest, and anticarcinogenic effects in human prostate carcinoma DU145 cells. Cancer Res. 58(9): 1920-1929.
Zi X., Zhang J., Agarwal R., et al 2000. Silibinin up-regulates insulin-like growth factor-binding protein 3 expression and inhibits proliferation of androgen-independent prostate cancer cells .Cancer Res. 60(20): 5617-5620.