Apatinib对卵巢癌细胞A2780增殖及紫杉醇敏感性的影响
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摘要
目的:研究阿帕替尼(apatinib)对卵巢癌细胞A2780增殖及紫杉醇敏感性的影响,并探讨其相关机制。方法:CCK-8法检测apatinib对A2780细胞增殖的影响,克隆形成实验检测apatinib对A2780细胞增殖能力的作用,流式细胞术检测apatinib对A2780细胞凋亡和细胞周期分布的影响,Western blot法检测apatinib靶蛋白。结果:与对照组比较,apatinib明显抑制卵巢癌A2780细胞的增殖及克隆形成(P<0.01)。Apatinib作用24h后,A2780细胞凋亡率明显增加(P<0.01),呈浓度依赖性的细胞周期阻滞。Apatinib诱导A2780细胞中CDK2表达下降和p21表达上升。小剂量apatinib显著提高A2780细胞对紫杉醇的敏感性。结论:Apatinib可显著抑制卵巢癌细胞的增殖并增强其对紫杉醇的敏感性。
Objective: To investigate the suppressive effects of apatinib in human ovarian cancer cell line-A2780.Methods: CCK-8 assay was used to detect the effects of apatinib on cellular growth and chemo-sensitivity.Colony formation assay was performed to detect the effects of apatinib on cellular abilities to form clones.Flow cytometric analysis was used to determine the alterations of apoptosis and cell cycle distribution.The expressions of key proteins were detected by Western blot.Results: Compared with the control group,apatinib could suppress the growth and impair the colony formation in A2780 cells( P<0.01).The 24 hour treatment with apatinib significantly induced cellular apoptosis( P<0.01),and caused cell cycle arrest in a dose-dependent manner.According to Western blot,the expression of cycle related proteins were notably influenced by Apatinib,CDK2 was downregulated while p21 was upregulated. Moreover,a low dose of apatinib could dramatically increase cellular sensitivity to paclitaxel.Conclusion: Apatinib could suppress cellular proliferation and synergize with paclitaxel in A2780 cells.
Objective: To investigate the suppressive effects of apatinib in human ovarian cancer cell line-A2780.Methods: CCK-8 assay was used to detect the effects of apatinib on cellular growth and chemo-sensitivity.Colony formation assay was performed to detect the effects of apatinib on cellular abilities to form clones.Flow cytometric analysis was used to determine the alterations of apoptosis and cell cycle distribution.The expressions of key proteins were detected by Western blot.Results: Compared with the control group,apatinib could suppress the growth and impair the colony formation in A2780 cells( P<0.01).The 24 hour treatment with apatinib significantly induced cellular apoptosis( P<0.01),and caused cell cycle arrest in a dose-dependent manner.According to Western blot,the expression of cycle related proteins were notably influenced by Apatinib,CDK2 was downregulated while p21 was upregulated. Moreover,a low dose of apatinib could dramatically increase cellular sensitivity to paclitaxel.Conclusion: Apatinib could suppress cellular proliferation and synergize with paclitaxel in A2780 cells.
引文
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[2]Ferlay J,Soerjomataram I,Dikshit R,et al.Cancer incidence and mortality worldwide:sources,methods and major patterns in GLOBOCAN 2012[J].Int J Cancer,2015,136(5):E359-386
[3]连丽娟.林巧稚妇科肿瘤学[M].第4版.北京:人民卫生出版社
[4]Chen W,Zheng R,Baade PD,et al.Cancer statistics in China,2015[J].CA Cancer J Clin.2016,66(2):115-132
[5]Rossi L,Verrico M,Zaccarelli E,et al.Bevacizumab in ovarian cancer:A critical review of phase III studies[J].Oncotarget,2017,8(7):12389-12405
[6]Bitler BG,Watson ZL,Wheeler LJ,et al.PARP inhibitors:Clinical utility and possibilities of overcoming resistance[J].Gynecol Oncol,2017,147(3):695-704
[7]Tian S,Quan H,Xie C,et al.YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo[J].Cancer Sci,2011,102(7):1374-1380
[8]Mi YJ,Liang YJ,Huang HB,et al.Apatinib(YN968D1)reverses multidrug resistance by inhibiting the efflux function of multiple ATP-binding cassette transporters[J].Cancer Res,2010,70(20):7981-7991
[9]Jin Z,Cheng X,Feng H,et al.Apatinib inhibits angiogenesis via suppressing akt/gsk3β/ang signaling pathway in anaplastic thyroid cancer[J].Cell Physiol Biochem,2017,44(4):1471-1484
[10]Li J,Qin S,Xu J,et al.Randomized,double-blind,placebo-controlled phase iii trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction[J].J Clin Oncol,2016,34(13):1448-1454
[11]Miao M,Deng G,Luo S,et al.A phase II study of apatinib in patients with recurrent epithelial ovarian cancer[J].Gynecol Oncol,2017[Epub ahead of print]
[12]Eisenhauer EA.Real-world evidence in the treatment of ovarian cancer[J].Ann Oncol,2017,28(suppl_8):viii61-viii65
[13]Hanahan D,Weinberg RA.Hallmarks of cancer:the next generation[J].Cell,2011,144(5):646-674
[14]Penson RT,Huang HQ,Wenzel LB,et al.Bevacizumab for advanced cervical cancer:patient-reported outcomes of a randomised,phase 3 trial(NRG Oncology-Gynecologic Oncology Group protocol 240)[J].Lancet Oncol,2015,16(3):301-311
[15]Tewari KS,Sill MW,Long HJ,et al.Improved survival with bevacizumab in advanced cervical cancer[J].N Engl J Med,2014,370(8):734-743