天然醌类化合物抗肺癌机制研究进展
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摘要
肺癌是常见恶性肿瘤,具有高发病率、高死亡率的特点,放化疗目前仍是其主要治疗方式,但是放化疗带来的副作用不容忽视,亟需寻找毒性低,作用强并且对癌细胞具有靶向性的抗癌化合物,于是数量众多的天然产物来源化合物的抗癌作用受到越来越多的关注。他们结构多样,种类丰富但比天然植物成分简单,作用明确,这利于研究并且在应用时,富集的成分比天然植物的药理作用和临床疗效更强。醌类化合物属于天然生物活性分子,广泛存在于100多种高等和低等植物的各个部位中,包括萘醌、菲醌、苯醌和蒽醌,大多数具有抗肿瘤作用,它在许多癌症中都有应用和研究,其中在肺癌中的研究已经有很多,作用机制涉及多种途径,发挥促进凋亡、抑制增殖,诱导自噬,抑制血管生成和细胞侵袭迁移等多种作用,有些药物在与其他药物联用时还具有增强抗肿瘤作用的效果。随着研究的增多,许多合成的结构类似的醌类衍生物也增加了抗肺癌醌类化合物的多样可选性,醌类化合物在肺癌中具有广泛的应用前景。在查阅大量文献的基础上,现对目前醌类化合物抗肺癌的分子机制研究进行综述,总结不同作用的常见研究靶点,分析醌类化合物药理作用与抗肺癌作用之间的关系,提出可深入研究方向的思考,为后续其他醌类化合物的研究和开发作参考。
Lung cancer is a common malignancy with a high morbidity and high mortality. Although chemoradiotherapy is still the main therapy,the side effects caused by radiotherapy and chemotherapy cannot be ignored. There is an urgent need to find a targeted anti-cancer compound with a low toxicity and strong effect.Therefore,a large number of natural product-derived compounds have received increasing attention for their anticancer effect. They are diverse in structure,rich in variety but simpler in composition than natural plants,with a clear efficacy. This facilitates research,and the enriched ingredients have stronger pharmacological effect and clinical efficacy than natural plants. Quinonoids are natural bioactive molecules that widely exist in more than 100 species of higher and lower plants, including naphthoquinones, phenanthrenequinones, benzoquinones and pyrenes. Most of them have anti-tumor effect. They are applied and studied in many cancers,especially lung cancer; and the mechanism of action involves multiple pathways,which play a role in promoting apoptosis,inhibiting proliferation,inducing autophagy,inhibiting angiogenesis and cell invasion and migration. When they are used in combination with other drugs,there is also an anti-tumor effect. With the development of researches,many synthetic quinonoid derivatives with similar structures also increase the diversity of anti-cancer steroids,and quinonoids have broad application prospects in lung cancer. On the basis of a large amount of literature,this article reviews current studies on the molecular mechanisms of antitumor activity of quinonoids,summarizes the common research targets with different effect,and analyzes the relationship between the pharmacological effects and antilung cancer effects of quinonoids,and proposes the direction of further research,so as to provide the reference for the follow-up research and development of other quinonoids.
Lung cancer is a common malignancy with a high morbidity and high mortality. Although chemoradiotherapy is still the main therapy,the side effects caused by radiotherapy and chemotherapy cannot be ignored. There is an urgent need to find a targeted anti-cancer compound with a low toxicity and strong effect.Therefore,a large number of natural product-derived compounds have received increasing attention for their anticancer effect. They are diverse in structure,rich in variety but simpler in composition than natural plants,with a clear efficacy. This facilitates research,and the enriched ingredients have stronger pharmacological effect and clinical efficacy than natural plants. Quinonoids are natural bioactive molecules that widely exist in more than 100 species of higher and lower plants, including naphthoquinones, phenanthrenequinones, benzoquinones and pyrenes. Most of them have anti-tumor effect. They are applied and studied in many cancers,especially lung cancer; and the mechanism of action involves multiple pathways,which play a role in promoting apoptosis,inhibiting proliferation,inducing autophagy,inhibiting angiogenesis and cell invasion and migration. When they are used in combination with other drugs,there is also an anti-tumor effect. With the development of researches,many synthetic quinonoid derivatives with similar structures also increase the diversity of anti-cancer steroids,and quinonoids have broad application prospects in lung cancer. On the basis of a large amount of literature,this article reviews current studies on the molecular mechanisms of antitumor activity of quinonoids,summarizes the common research targets with different effect,and analyzes the relationship between the pharmacological effects and antilung cancer effects of quinonoids,and proposes the direction of further research,so as to provide the reference for the follow-up research and development of other quinonoids.
引文
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[5] Asche C. Antitumour quinones[J]. Mini Rev Med Chem,2005,5(5):449-467.
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[8] LI W Y,Ng Y F,ZHANG H,et al. Emodin elicits cytotoxicity in human lung adenocarcinoma A549 cells throughinducingapoptosis[J].Inflammopharmacology,2014,22(2):127-134.
[9] SU J,YAN Y,QU J,et al. Emodin induces apoptosis of lung cancer cells through ER stress and the TRIB3/NF-κB pathway[J]. Oncol Rep,2017, 37(3):1565-1572.
[10] LAI J M,CHANG J T,WEN C L,et al. Emodin induces a reactive oxygen species-dependent and ATMp53-Bax mediated cytotoxicity in lung cancer cells[J].Eur J Pharmacol,2009,623(1/3):1-9.
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[12] TANG Q,WU J,ZHENG F,et al. Emodin increases expression of insulin-like growth factor binding protein 1through activation of MEK/ERK/AMPK and interaction of PPAR and Sp1 in lung cancer[J]. Cell Physiol Biochem,2016,41(1):339-357.
[13] HE L,BI J J,GUO Q,et al. Effects of emodin extracted from Chinese herbs on proliferation of nonsmall cell lung cancer and underlying mechanisms[J].Asian Pac J Cancer Prev,2012,13(4):1505-1510.
[14] Ko J C,SU Y J,LIN S T,et al. Suppression of ERCC1and Rad51 expression through ERK1/2 inactivation is essential in emodin-mediated cytotoxicity in human nonsmall cell lung cancer cells[J]. Biochem Pharmacol,2010,79(4):655-664.
[15] HE F L,WANG L,ZHANG X K,et al. Emodin induces apoptosis of cancer cells and inhibits retinoid X receptor transcriptional activity[J]. Acta Pharmaceutica Sinica B,2008,43(4):350-355.
[16] XU T P,SHEN H,LIU L X,et al. Plumbagin from Plumbago Zeylanica L induces apoptosis in human nonsmall cell lung cancer cell lines through NF-κB inactivation[J]. Asian Pac J Cancer Prev,2013,14(4):2325-2331.
[17] WANG H B,MA X Q.β,β-Dimethylacrylshikonin induces mitochondria-dependent apoptosis of human lung adenocarcinoma cells in vitro via p38 pathway activation[J]. Acta Pharmacol Sin,2015,36(1):131-138.
[18] NI C H,YU C S,LU H F,et al. Chrysophanol-induced cell death(necrosis)in human lung cancer A549 cells is mediated through increasing reactive oxygen species and decreasing the level of mitochondrial membrane potential[J]. Environ Toxicol, 2014, 29(7):740-749.
[19] MA Z L,ZHANG B J,WANG D T,et al. Tanshinones suppress AURKA through up-regulation of miR-32expression in non-small cell lung cancer[J].Oncotarget,2015,6(24):20111-20120.
[20] ZHANG J,WANG J,JIANG J Y,et al. TanshinoneⅡA induces cytochrome c-mediated Caspase cascade apoptosis in A549 human lung cancer cells via the JNK pathway[J]. Int J Oncol,2014,45(2):683-690.
[21] Hsia T C,YANG J S,CHEN G W,et al. The roles of endoplasmic reticulum stress and Ca2+on rhein-induced apoptosis in A-549 human lung cancer cells[J].Anticancer Res,2009,29(1):309-318.
[22] ZHANG X B,ZOU C L,DUAN Y X,et al. Activity guided isolation and modification of juglone from Juglans regia as potent cytotoxic agent against lung cancer cell lines[J]. BMC Complement Altern Med,2015,15(1):1-8.
[23] WAN L,ZHANG L,FAN K,et al. Aloin promotes A549 cell apoptosis via the reactive oxygen speciesamitogen activated protein kinase signaling pathway and p53 phosphorylation[J]. Mol Med Rep,2017,16(5):5759-5768.
[24] WU Y Y,ZHANG J H,GAO J H,et al. Aloe-emodin(AE)nanoparticles suppresses proliferation and induces apoptosis in human lung squamous carcinoma via ROS generation in vitro and in vivo[J]. Biochem Biophys Res Commun,2017,490(3):601-607.
[25] LI H Z, WU C H, CHANG S P. Release of nucleophosmin from the nucleus:involvement in aloeemodin-induced human lung nonsmall carcinoma cell apoptosis[J]. Int J Cancer,2004,113(6):971-976.
[26] Lee H Z,YANG W H,Hour M J,et al. Photodynamic activity of aloe-emodin induces resensitization of lung cancer cells to anoikis[J]. Eur J Pharmacol,2010,648(1/3):50-58.
[27] Lee H Z,Lin C J,YANG W H,et al. Aloe-emodin induced DNA damage through generation of reactive oxygen species in human lung carcinoma cells[J].Cancer Lett,2006,239(1):55-63.
[28] CHANG W T,YOU B J,YANG W H,et al. Protein kinase C delta-mediated cytoskeleton remodeling is involved in aloe-emodin-induced photokilling of human lung cancer cells[J]. Anticancer Res,2012,32(9):3707-3713.
[29] LAI M Y, HOU M J, Wingcheung L H, et al.Chaperones are the target in aloe-emodin-induced human lung nonsmall carcinoma H460 cell apoptosis[J]. Eur J Pharmacol,2007,573(1/3):1-10.
[30] ZHANG Y W,ZHANG Z X,MIAO Z H,et al. The telomeric protein TRF2 is critical for the protection of A549 cells from both telomere erosion and DNA doublestrand breaks driven by salvicine[J]. Mol Pharmacol,2007,73(3):824-832.
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