虎杖苷抗肿瘤作用及机制研究
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摘要
恶性肿瘤是严重威胁人类健康和生命的疾病，由于人口增长、老龄化和不良生活习惯的影响，近年来在全世界范围内恶性肿瘤的发病率持续上升。恶性肿瘤已成为发达国家和发展中国家的首位死因。乳腺癌是世界各地女性最常见的恶性肿瘤之一，占女性新发恶性肿瘤的23%，具有发病率高、侵袭性强、病程进展缓慢等特点。肺癌则是男性中最常见的恶性肿瘤，是男性癌性死亡的首位原因，女性癌性死亡的第二大肿瘤。
目前对于恶性肿瘤的主要治疗方法包括：手术，放射治疗，化疗和分子靶向治疗。化疗在恶性肿瘤治疗中仍处于基础地位，但目前临床上广泛使用的化疗药物疗效有限，毒性作用较大，经几次应用后还会发生耐药。近年来，采用传统中药等植物提取物探讨恶性肿瘤治疗的新途径引起了人们的关注，从传统中药提取的抗肿瘤药物如冬凌草甲素、黄连素、姜黄素的体外实验表明可抑制多种肿瘤细胞的增殖，从植物中提取的紫杉醇、喜树碱、长春新碱等药物已在临床上广泛应用。因此筛选新型抗肿瘤的植物药，确定其抗肿瘤作用并探讨其机制，已成为当今肿瘤治疗研究领域的热点之一。
虎杖苷是从虎杖的干燥根茎中提取的第4种单体，又名白藜芦醇苷，现代药理学研究表明虎杖苷对心肌细胞、血管平滑肌细胞、抗血小板聚集、改善微循环等有显著作用，此外还能减轻多种因素造成的组织器官损伤，具有保护肝细胞，降血脂及抗脂质过氧化等作用。而对其抗肿瘤作用的研究报道仍较少，本课题是研究虎杖苷在乳腺癌细胞、肺癌中的生物学功能以及相关机制，旨为进一步开展虎杖苷抗肿瘤作用的基础和临床研究提供实验基础和理论依据。本课题实验内容主要分为五部分：
第一部分虎杖苷对恶性肿瘤增殖抑制效应的研究
目的：
研究虎杖苷在体内外对乳腺癌、肺癌生长的影响，并观察其对正常细胞的毒性和在体内的对实验动物的毒副作用。
方法：
应用MTT或CCK8法检测虎杖苷对10种不同来源的恶性肿瘤细胞及两种正常上皮细胞生存曲线的影响并比较了虎杖苷和白藜芦醇抑制肿瘤细胞生长的效力。应用流式细胞术分析虎杖苷对乳腺癌及肺癌细胞的细胞周期变化的影响及凋亡诱导情况。采用人肺癌细胞皮下移植动物模型观察虎杖苷对动物体内肿瘤生长的影响及其毒副作用。
结果：
虎杖苷对10种不同来源的恶性肿瘤细胞包括乳腺癌MCF-7、MDA-MB-231，肺癌A549、NCI-H1975、宫颈癌Hela、卵巢癌SKOV-3、肝癌SM7721、鼻咽癌CNE-1，白血病HL-60及K562细胞均具有明显的抑制其生长的作用，且生长抑制作用呈剂量和时间-效应关系。虎杖苷对正常乳腺上皮细胞MCF-10A及肺支气管上皮细胞HBE的毒性作用小于相应的肿瘤细胞。虎杖苷对乳腺癌及肺癌细胞的生长抑制作用明显强于其糖配基白藜芦醇。流式细胞术的结果显示虎杖苷可引起肿瘤细胞阻滞于细胞周期进程的S期，虎杖苷诱导肿瘤细胞发生凋亡。动物实验结果显示虎杖苷可明显抑制裸鼠移植瘤的生长且未见明显毒副反应。
第二部分虎杖苷抗肿瘤作用的分子机制研究
目的：
研究虎杖苷抑制肿瘤细胞生长、引起细胞周期阻滞及诱导肿瘤细胞凋亡的分子机制。
方法：
采用人磷酸化激酶蛋白芯片及凋亡相关蛋白芯片检测经虎杖苷处理的乳腺癌细胞内磷酸化激酶及凋亡相关蛋白的变化。应用Western blot实验验证和检测与细胞生长、细胞周期进程和细胞凋亡相关蛋白的变化。应用MTT法及流式细胞术检测PI3K、Erk、JNK、P38抑制剂对虎杖苷抗肿瘤作用的影响。
结果：
虎杖苷处理后的乳腺癌细胞内CREB的活性受到抑制，且抑制作用在虎杖苷作用后2小时即发生并一直持续至40小时。细胞周期相关蛋白Cyclin D1的表达在虎杖苷处理后的乳腺癌及肺癌细胞表达明显下降。虎杖苷处理后的乳腺癌细胞内源性和外源性凋亡途径均被激活。PI3K、Erk、JNK、P38抑制剂对虎杖苷抑制肿瘤细胞生长、引起细胞周期阻滞及诱导肿瘤细胞凋亡的作用无明显影响。
第三部分虎杖苷对肿瘤细胞转移的影响及分子机制研究
目的：
研究虎杖苷对如乳腺癌及肺癌细胞转移及侵袭的影响，并对其分子机制进行初步探讨。
方法：
应用伤口愈合实验及Transwell细胞迁移实验观察虎杖苷对细胞迁移能力的影响。应用肿瘤细胞粘壁实验观察虎杖苷对肿瘤细胞粘附能力的影响。采用Transwell细胞侵袭实验观察虎杖苷对肿瘤细胞侵袭能力的影响。采用Western blot实验检测与细胞转移浸润相关蛋白表达的变化。
结果：
伤口愈合实验及Transwell细胞迁移实验显示虎杖苷可抑制乳腺癌及肺癌细胞的迁移，粘壁实验结果显示虎杖苷可抑制乳腺癌MDA-MB-231细胞的粘附能力，Transwell细胞侵袭实验结果显示虎杖苷可明显抑制乳腺癌细胞的侵袭能力。Western blot的实验结果显示经虎杖苷处理后的乳腺癌细胞E-cadherin、-catenin的表达上调，N-cadherin的表达下调，MMP-2、MMP-9的表达无明显变化。
第四部分虎杖苷对阿霉素耐药乳腺癌细胞的生长抑制作用研究
目的：
研究虎杖苷对乳腺癌耐阿霉素细胞MCF-7/ADR增殖、细胞周期及凋亡的影响，并初步探讨其分子机制。
方法：
应用MTT法检测虎杖苷对乳腺癌耐阿霉素细胞MCF-7/ADR的生存曲线的影响，应用流式细胞术检测虎杖苷处理MCF-7/ADR细胞后细胞周期的变化和凋亡发生率，应用Western blot实验检测虎杖苷对MCF-7/ADR细胞的细胞周期、凋亡相关蛋白的影响。
结果：
MCF-7/ADR细胞除了对阿霉素耐药外还对吉西他滨和紫杉醇耐受，虎杖苷可抑制MCF-7/ADR的生长且其抑制作用与MCF-7细胞相比无明显差异。流式细胞术的结果显示虎杖苷引起MCF-7/ADR细胞发生细胞周期G0/G1期阻滞，虎杖苷诱导MCF-7/ADR细胞发生凋亡，且凋亡诱导效应呈剂量依赖。Western blot实验显示虎杖苷处理的MCF-7/ADR细胞Bcl-2、CyclinD1及NF-B表达下降、Bax及Cleaved-PARP表达上调。
第五部分虎杖苷对晚期炎症因子HMGB1影响的研究
目的：
研究虎杖苷对LPS刺激巨噬细胞后晚期炎症因子HMGB1及多种早期炎症因子释放的影响。
方法：
应用Western blot实验检测虎杖苷及白藜芦醇对LPS刺激巨噬细胞产生的HMGB1的影响，应用Griess法检测虎杖苷对LPS刺激巨噬细胞产生的NO的影响，应用细胞因子芯片检测虎杖苷及白藜芦醇对LPS刺激巨噬细胞产生的多种早期炎症因子的影响。
结果：
LPS刺激巨噬细胞后，细胞释放大量HMGB1，虎杖苷在0.06和0.12mol/L的剂量范围内则可减少LPS所引起的HMGB1的释放,白藜芦醇在0.5-2.5mol/L的剂量范围内可抑制LPS诱导的HMGB1的释放。虎杖苷对LPS所引起的NO的释放无明显影响。细胞因子芯片的结果显示，虎杖苷及白藜芦醇在可抑制HMGB释放的浓度范围内对62种早期炎症因子无明显影响。
结论
(1)虎杖苷具有广谱的抑制肿瘤细胞增殖的作用，且虎杖苷在抑制肿瘤细胞生长的同时对正常细胞的毒性较小，在动物体内实验，虎杖苷可抑制裸鼠移植瘤的生长并对动物无明显毒副作用。虎杖苷通过导致细胞周期S期阻滞及诱导凋亡发挥抗肿瘤作用。虎杖苷抑制肿瘤细胞生长、引起细胞周期阻滞及诱导肿瘤细胞凋亡的机制可能与抑制CREB的活性，下调Cyclin D1，激活内外源性细胞凋亡信号通路有关。虎杖苷抗肿瘤作用与PI3K/AKT及MAPK信号通路及NF-B无关。
(2)在不明显影响细胞生长的浓度下，虎杖苷在体外可抑制乳腺癌和肺癌细胞的贴壁能力、迁移和侵袭能力，其抑制乳腺癌转移能力的机制可能与上调E-cadherin、-catenin蛋白，下调N-cadherin蛋白的表达有关。
(3)虎杖苷对乳腺癌耐阿霉素细胞仍具有增殖抑制作用，导致乳腺癌耐阿霉素MCF-7/ADR细胞细胞周期G0/G1期阻滞及发生凋亡，其机制可能上调Bax蛋白、激活PARP，下调Bcl-2及NF-B蛋白的表达有关。
(4)虎杖苷对LPS诱导巨噬细胞后晚期炎症因子HMGB1及多种早期炎症因子的产生无明显影响。
Cancer has become an increasing health threat worldwide as a result of populationaging and growth as well as adoption of cancer-associated lifestyle. Breast cancer is themost frequently diagnosed cancer and the leading cause of cancer death among women.Lung cancer is the most commonly diagnosed cancer and the leading cause of cancerdeath in men. Despite advances in all the standard treatments, such as surgery,radiotherapy, chemotherapy, molecular targeting therapy, or combined regiment, theoverall outcome is still poor due to metastasis, drug resistance, and recurrence. Thus thequest to find novel agents for cancer therapy is a never-ending venture.
With development of phytochemistry, more and more researchers pay theirattention to the importance of herbal plants． Famous examples of plant-basedtherapeutic anticancer drugs include camptothecin, etoposide, vincristine, and paclitaxel.These drugs have been use in cancer treatment for many years. Polydatin (PD) is one ofthe main effective elements of Polygonum cuspidatum. Pharmacological studies andclinical practice have demonstrated that polydatin has many biological functions, suchas protective effect against shock ischemia/reperfusion injury, congestive heart failure,and endometriosis. However, the effects of polydatin on human cancer cells have rarelybeen reported.
In this study, a series of methods, including MTT assay, in vitro wound healingassay, in vitro cellular adhesion assay, and Transewell migration and invasion assay,were employed to determine cell growth and proliferation, invasion and migration. Flowcytometry was used to determine alteration of cell cycle progression and apoptosis.Human phosphor-kinase array, human apoptosis array and western blot assays wereemployed to investigate expression of proteins related to cell growth, cell cycle, andapoptosis. In animal studies, nude mice lung cancer transplant models were used toinvestigate tumor growth.
As observed by MTT assay, polydatin has a broad spectrum of growth inhibition effects against10cancer cell lines. It is more potent to kill cancer cells than non-cancercells. It inhibited cell growth in a dose-and tome-dependent fashion. Animal studiesalso showed polydatin could inhibit tumor growth and did not have significant sideeffects. Flow cytometry assay indicated polydatin induced apoptosis and cell cycle Sphase arrest in breast and lung cancer cells. Human phosphor-kinase array, humanapoptosis array and western blot assays indicated the anti-proliferation and cell cyclearrest effects of polydatin might be associated with down regulation of pCREB andcyclinD1. Polydatin induced apoptosis through both intrinsic and extrinsic pathway. Baxis the major target in intrinsic pathway.
In breast and lung cancer cells, polydatin significantly decreased the ability of celladhesion, cell migration and invasion at non-toxic dosage. Up-regulation of E-Cadherin,
-Catenin and down-regulation of N-Cadherin partly contributed to these effects.Polydatin also showed great potential in inhibiting cell growth of adriamycin-resistantbreast cancer cells through inducing apoptosis and cell cycle G0/G1phase arrest.CyclinD1, Bcl-2, Bax and NF-B are involved in the inhibitory effect of polydatin inadriamycin-resistant breast cancer cells.
In conclusion, polydain not only inhibits cancer growth both in vitro and in vivo,but also reduces ability of cell adhesion, migration and invasion. Furthermore, polydatinmay inhibit proliferation of drug resistant cells. These studies, for the first time,demonstrated that polydatin might be a promising compound for breast and lung cancertreatment. Although the exact mechanisms need to be further investigated, multiplepathways involved in cell cycle progression and apoptosis including pCREB, cyclinD1and Bcl-2family have been identified in the this study.
目前对于恶性肿瘤的主要治疗方法包括：手术，放射治疗，化疗和分子靶向治疗。化疗在恶性肿瘤治疗中仍处于基础地位，但目前临床上广泛使用的化疗药物疗效有限，毒性作用较大，经几次应用后还会发生耐药。近年来，采用传统中药等植物提取物探讨恶性肿瘤治疗的新途径引起了人们的关注，从传统中药提取的抗肿瘤药物如冬凌草甲素、黄连素、姜黄素的体外实验表明可抑制多种肿瘤细胞的增殖，从植物中提取的紫杉醇、喜树碱、长春新碱等药物已在临床上广泛应用。因此筛选新型抗肿瘤的植物药，确定其抗肿瘤作用并探讨其机制，已成为当今肿瘤治疗研究领域的热点之一。
虎杖苷是从虎杖的干燥根茎中提取的第4种单体，又名白藜芦醇苷，现代药理学研究表明虎杖苷对心肌细胞、血管平滑肌细胞、抗血小板聚集、改善微循环等有显著作用，此外还能减轻多种因素造成的组织器官损伤，具有保护肝细胞，降血脂及抗脂质过氧化等作用。而对其抗肿瘤作用的研究报道仍较少，本课题是研究虎杖苷在乳腺癌细胞、肺癌中的生物学功能以及相关机制，旨为进一步开展虎杖苷抗肿瘤作用的基础和临床研究提供实验基础和理论依据。本课题实验内容主要分为五部分：
第一部分虎杖苷对恶性肿瘤增殖抑制效应的研究
目的：
研究虎杖苷在体内外对乳腺癌、肺癌生长的影响，并观察其对正常细胞的毒性和在体内的对实验动物的毒副作用。
方法：
应用MTT或CCK8法检测虎杖苷对10种不同来源的恶性肿瘤细胞及两种正常上皮细胞生存曲线的影响并比较了虎杖苷和白藜芦醇抑制肿瘤细胞生长的效力。应用流式细胞术分析虎杖苷对乳腺癌及肺癌细胞的细胞周期变化的影响及凋亡诱导情况。采用人肺癌细胞皮下移植动物模型观察虎杖苷对动物体内肿瘤生长的影响及其毒副作用。
结果：
虎杖苷对10种不同来源的恶性肿瘤细胞包括乳腺癌MCF-7、MDA-MB-231，肺癌A549、NCI-H1975、宫颈癌Hela、卵巢癌SKOV-3、肝癌SM7721、鼻咽癌CNE-1，白血病HL-60及K562细胞均具有明显的抑制其生长的作用，且生长抑制作用呈剂量和时间-效应关系。虎杖苷对正常乳腺上皮细胞MCF-10A及肺支气管上皮细胞HBE的毒性作用小于相应的肿瘤细胞。虎杖苷对乳腺癌及肺癌细胞的生长抑制作用明显强于其糖配基白藜芦醇。流式细胞术的结果显示虎杖苷可引起肿瘤细胞阻滞于细胞周期进程的S期，虎杖苷诱导肿瘤细胞发生凋亡。动物实验结果显示虎杖苷可明显抑制裸鼠移植瘤的生长且未见明显毒副反应。
第二部分虎杖苷抗肿瘤作用的分子机制研究
目的：
研究虎杖苷抑制肿瘤细胞生长、引起细胞周期阻滞及诱导肿瘤细胞凋亡的分子机制。
方法：
采用人磷酸化激酶蛋白芯片及凋亡相关蛋白芯片检测经虎杖苷处理的乳腺癌细胞内磷酸化激酶及凋亡相关蛋白的变化。应用Western blot实验验证和检测与细胞生长、细胞周期进程和细胞凋亡相关蛋白的变化。应用MTT法及流式细胞术检测PI3K、Erk、JNK、P38抑制剂对虎杖苷抗肿瘤作用的影响。
结果：
虎杖苷处理后的乳腺癌细胞内CREB的活性受到抑制，且抑制作用在虎杖苷作用后2小时即发生并一直持续至40小时。细胞周期相关蛋白Cyclin D1的表达在虎杖苷处理后的乳腺癌及肺癌细胞表达明显下降。虎杖苷处理后的乳腺癌细胞内源性和外源性凋亡途径均被激活。PI3K、Erk、JNK、P38抑制剂对虎杖苷抑制肿瘤细胞生长、引起细胞周期阻滞及诱导肿瘤细胞凋亡的作用无明显影响。
第三部分虎杖苷对肿瘤细胞转移的影响及分子机制研究
目的：
研究虎杖苷对如乳腺癌及肺癌细胞转移及侵袭的影响，并对其分子机制进行初步探讨。
方法：
应用伤口愈合实验及Transwell细胞迁移实验观察虎杖苷对细胞迁移能力的影响。应用肿瘤细胞粘壁实验观察虎杖苷对肿瘤细胞粘附能力的影响。采用Transwell细胞侵袭实验观察虎杖苷对肿瘤细胞侵袭能力的影响。采用Western blot实验检测与细胞转移浸润相关蛋白表达的变化。
结果：
伤口愈合实验及Transwell细胞迁移实验显示虎杖苷可抑制乳腺癌及肺癌细胞的迁移，粘壁实验结果显示虎杖苷可抑制乳腺癌MDA-MB-231细胞的粘附能力，Transwell细胞侵袭实验结果显示虎杖苷可明显抑制乳腺癌细胞的侵袭能力。Western blot的实验结果显示经虎杖苷处理后的乳腺癌细胞E-cadherin、-catenin的表达上调，N-cadherin的表达下调，MMP-2、MMP-9的表达无明显变化。
第四部分虎杖苷对阿霉素耐药乳腺癌细胞的生长抑制作用研究
目的：
研究虎杖苷对乳腺癌耐阿霉素细胞MCF-7/ADR增殖、细胞周期及凋亡的影响，并初步探讨其分子机制。
方法：
应用MTT法检测虎杖苷对乳腺癌耐阿霉素细胞MCF-7/ADR的生存曲线的影响，应用流式细胞术检测虎杖苷处理MCF-7/ADR细胞后细胞周期的变化和凋亡发生率，应用Western blot实验检测虎杖苷对MCF-7/ADR细胞的细胞周期、凋亡相关蛋白的影响。
结果：
MCF-7/ADR细胞除了对阿霉素耐药外还对吉西他滨和紫杉醇耐受，虎杖苷可抑制MCF-7/ADR的生长且其抑制作用与MCF-7细胞相比无明显差异。流式细胞术的结果显示虎杖苷引起MCF-7/ADR细胞发生细胞周期G0/G1期阻滞，虎杖苷诱导MCF-7/ADR细胞发生凋亡，且凋亡诱导效应呈剂量依赖。Western blot实验显示虎杖苷处理的MCF-7/ADR细胞Bcl-2、CyclinD1及NF-B表达下降、Bax及Cleaved-PARP表达上调。
第五部分虎杖苷对晚期炎症因子HMGB1影响的研究
目的：
研究虎杖苷对LPS刺激巨噬细胞后晚期炎症因子HMGB1及多种早期炎症因子释放的影响。
方法：
应用Western blot实验检测虎杖苷及白藜芦醇对LPS刺激巨噬细胞产生的HMGB1的影响，应用Griess法检测虎杖苷对LPS刺激巨噬细胞产生的NO的影响，应用细胞因子芯片检测虎杖苷及白藜芦醇对LPS刺激巨噬细胞产生的多种早期炎症因子的影响。
结果：
LPS刺激巨噬细胞后，细胞释放大量HMGB1，虎杖苷在0.06和0.12mol/L的剂量范围内则可减少LPS所引起的HMGB1的释放,白藜芦醇在0.5-2.5mol/L的剂量范围内可抑制LPS诱导的HMGB1的释放。虎杖苷对LPS所引起的NO的释放无明显影响。细胞因子芯片的结果显示，虎杖苷及白藜芦醇在可抑制HMGB释放的浓度范围内对62种早期炎症因子无明显影响。
结论
(1)虎杖苷具有广谱的抑制肿瘤细胞增殖的作用，且虎杖苷在抑制肿瘤细胞生长的同时对正常细胞的毒性较小，在动物体内实验，虎杖苷可抑制裸鼠移植瘤的生长并对动物无明显毒副作用。虎杖苷通过导致细胞周期S期阻滞及诱导凋亡发挥抗肿瘤作用。虎杖苷抑制肿瘤细胞生长、引起细胞周期阻滞及诱导肿瘤细胞凋亡的机制可能与抑制CREB的活性，下调Cyclin D1，激活内外源性细胞凋亡信号通路有关。虎杖苷抗肿瘤作用与PI3K/AKT及MAPK信号通路及NF-B无关。
(2)在不明显影响细胞生长的浓度下，虎杖苷在体外可抑制乳腺癌和肺癌细胞的贴壁能力、迁移和侵袭能力，其抑制乳腺癌转移能力的机制可能与上调E-cadherin、-catenin蛋白，下调N-cadherin蛋白的表达有关。
(3)虎杖苷对乳腺癌耐阿霉素细胞仍具有增殖抑制作用，导致乳腺癌耐阿霉素MCF-7/ADR细胞细胞周期G0/G1期阻滞及发生凋亡，其机制可能上调Bax蛋白、激活PARP，下调Bcl-2及NF-B蛋白的表达有关。
(4)虎杖苷对LPS诱导巨噬细胞后晚期炎症因子HMGB1及多种早期炎症因子的产生无明显影响。
Cancer has become an increasing health threat worldwide as a result of populationaging and growth as well as adoption of cancer-associated lifestyle. Breast cancer is themost frequently diagnosed cancer and the leading cause of cancer death among women.Lung cancer is the most commonly diagnosed cancer and the leading cause of cancerdeath in men. Despite advances in all the standard treatments, such as surgery,radiotherapy, chemotherapy, molecular targeting therapy, or combined regiment, theoverall outcome is still poor due to metastasis, drug resistance, and recurrence. Thus thequest to find novel agents for cancer therapy is a never-ending venture.
With development of phytochemistry, more and more researchers pay theirattention to the importance of herbal plants． Famous examples of plant-basedtherapeutic anticancer drugs include camptothecin, etoposide, vincristine, and paclitaxel.These drugs have been use in cancer treatment for many years. Polydatin (PD) is one ofthe main effective elements of Polygonum cuspidatum. Pharmacological studies andclinical practice have demonstrated that polydatin has many biological functions, suchas protective effect against shock ischemia/reperfusion injury, congestive heart failure,and endometriosis. However, the effects of polydatin on human cancer cells have rarelybeen reported.
In this study, a series of methods, including MTT assay, in vitro wound healingassay, in vitro cellular adhesion assay, and Transewell migration and invasion assay,were employed to determine cell growth and proliferation, invasion and migration. Flowcytometry was used to determine alteration of cell cycle progression and apoptosis.Human phosphor-kinase array, human apoptosis array and western blot assays wereemployed to investigate expression of proteins related to cell growth, cell cycle, andapoptosis. In animal studies, nude mice lung cancer transplant models were used toinvestigate tumor growth.
As observed by MTT assay, polydatin has a broad spectrum of growth inhibition effects against10cancer cell lines. It is more potent to kill cancer cells than non-cancercells. It inhibited cell growth in a dose-and tome-dependent fashion. Animal studiesalso showed polydatin could inhibit tumor growth and did not have significant sideeffects. Flow cytometry assay indicated polydatin induced apoptosis and cell cycle Sphase arrest in breast and lung cancer cells. Human phosphor-kinase array, humanapoptosis array and western blot assays indicated the anti-proliferation and cell cyclearrest effects of polydatin might be associated with down regulation of pCREB andcyclinD1. Polydatin induced apoptosis through both intrinsic and extrinsic pathway. Baxis the major target in intrinsic pathway.
In breast and lung cancer cells, polydatin significantly decreased the ability of celladhesion, cell migration and invasion at non-toxic dosage. Up-regulation of E-Cadherin,
-Catenin and down-regulation of N-Cadherin partly contributed to these effects.Polydatin also showed great potential in inhibiting cell growth of adriamycin-resistantbreast cancer cells through inducing apoptosis and cell cycle G0/G1phase arrest.CyclinD1, Bcl-2, Bax and NF-B are involved in the inhibitory effect of polydatin inadriamycin-resistant breast cancer cells.
In conclusion, polydain not only inhibits cancer growth both in vitro and in vivo,but also reduces ability of cell adhesion, migration and invasion. Furthermore, polydatinmay inhibit proliferation of drug resistant cells. These studies, for the first time,demonstrated that polydatin might be a promising compound for breast and lung cancertreatment. Although the exact mechanisms need to be further investigated, multiplepathways involved in cell cycle progression and apoptosis including pCREB, cyclinD1and Bcl-2family have been identified in the this study.
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