二甲双胍提高肝癌细胞的药物敏感性及其作用机制
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摘要
目的探究二甲双胍是否可增强肝癌细胞对索拉菲尼的敏感性及其相关机制。方法 CCK-8及流式细胞术检测二甲双胍联合索拉菲尼处理或单一索拉菲尼处理后肝癌HepG2细胞的增殖活性和凋亡;Western blot技术检测凋亡相关蛋白及PI3K/AKT/mTOR通路的激活情况。结果较索拉菲尼组相比,二甲双胍+索拉菲尼组细胞增殖活性降低,凋亡上升,Bcl-2表达降低,而Bax、Caspase3表达升高,且p-PI3K、p-AKT及p-mTOR的蛋白表达水平升高。结论二甲双胍可增强肝癌细胞对索拉菲尼的药物敏感性,这可能与PI3K/AKT/mTOR通路和上皮间充质转化过程抑制相关。
Objective To explore the effect and mechanism of metformin on sorafenib sensitivity of hepatocellular carcinoma cells.Methods CCK-8 and flow cytometry assay were used to assess cell proliferation and apoptosis after hepatocellular carcinoma HepG2 cells were treated with metformin+sorafenib or sorafenib;Western blot was used to test the expression of proteins related to cell apoptosis or to evaluate the activitaion of PI3 K/AKT/mTOR signaling.Results Compared with sorafenib,cell proliferation was inhibited,cell apoptosis was enhanced,the expression of Bcl-2 was decreased while Bax and caspase3 expression was elevated in metformin+sorafenib group,as well as increased expression of p-PI3 K、p-AKT and p-mTOR protein.Conclusion Metformin enhances the drug sensitivity of hepatocellular carcinoma cells to sorafenib,which might be associated with the inhibition of PI3 K/AKT/mTOR signaling and epithelial mesenchymal transformation.
Objective To explore the effect and mechanism of metformin on sorafenib sensitivity of hepatocellular carcinoma cells.Methods CCK-8 and flow cytometry assay were used to assess cell proliferation and apoptosis after hepatocellular carcinoma HepG2 cells were treated with metformin+sorafenib or sorafenib;Western blot was used to test the expression of proteins related to cell apoptosis or to evaluate the activitaion of PI3 K/AKT/mTOR signaling.Results Compared with sorafenib,cell proliferation was inhibited,cell apoptosis was enhanced,the expression of Bcl-2 was decreased while Bax and caspase3 expression was elevated in metformin+sorafenib group,as well as increased expression of p-PI3 K、p-AKT and p-mTOR protein.Conclusion Metformin enhances the drug sensitivity of hepatocellular carcinoma cells to sorafenib,which might be associated with the inhibition of PI3 K/AKT/mTOR signaling and epithelial mesenchymal transformation.
引文
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[10]吴诗文,张自森,刘谦,等.二甲双胍联合化疗药物对人胃癌AGS细胞的作用[J].郑州大学学报(医学版),2017,(1):37.
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[12]张敏,李晓明,路秀英.二甲双胍对下咽癌Fadu细胞的增殖抑制作用及其对化疗药物敏感性影响的研究[J].中华耳鼻咽喉头颈外科杂志,2014,49(4):317.
[13]孙英明,谢敏,孙丽娟,等.二甲双胍调控AKT/MDR-1增强人结肠癌细胞HT-29对5-FU药物敏感性机制探讨[J].现代肿瘤医学,2015,(24):3560.
[14]Wang LW,Li ZS,Zou DW,et al.Metformin induces apoptosis of pancreatic cancer cells[J].World J Gastroenterol,2008,14(47):7192.
[15]舒婷,万福生.PI3K/Akt/mTOR信号通路与自噬及肿瘤的关系[J].中国生物化学与分子生物学报,2016,(11):1192.
[2]Siegel R L,Miller K D,Jemal A.Cancer Statistics,2017[J].Ca Cancer J Clin,2017,67(1):7.
[3]Gauthier A,Ho M.Role of sorafenib in the treatment of advanced hepatocellular carcinoma:An update[J].Hepatol Res,2013,43(2):147.
[4]Karnevi E,Said K,Andersson R,et al.Metformin-mediated growth inhibition involves suppression of the IGF-I receptor signalling pathway in human pancreatic cancer cells[J].BMC Cancer,2013,10(13):235.
[5]Rattan R,Graham R P,Maguire J L,et al.Metformin suppresses ovarian cancer growth and metastasis with enhancement of cisplatin cytotoxicity in vivo[J].Neoplasia,2011,13(5):483.
[6]Decensi A,Puntoni M,Goodwin P,et al.Metformin and Cancer Risk in Diabetic Patients:A Systematic Review and Meta-analysis[J].Cancer Prevention Research,2010,3(11):1451.
[7]林芳,严威,文霆,等.二甲双胍体外诱导人肝癌Huh-7细胞凋亡及其作用机制[J].中华肿瘤杂志,2013(10):742.
[8]Zhang HH,Zhang Y,Cheng YN,et al.Metformin incombination with curcumin inhibits the growth,metastasis,and angiogenesis of hepatocellular carcinoma in vitro and in vivo[J].Mol Carcinog,2018,57(1):44.
[9]彭晓韧,刘燕,邹大进.二甲双胍对人肝癌细胞HepG2增殖及乙酰辅酶A羧化酶影响的实验研究[J].临床肿瘤学杂志,2015,(3):203.
[10]吴诗文,张自森,刘谦,等.二甲双胍联合化疗药物对人胃癌AGS细胞的作用[J].郑州大学学报(医学版),2017,(1):37.
[11]Uehara T,Mitsuhashi A,Tsuruoka N,et al.Metformin potentiates the anticancer effects of cisplatin under normoxic conditions in vitro[J].Oncol Rep,2015,33(2):744.
[12]张敏,李晓明,路秀英.二甲双胍对下咽癌Fadu细胞的增殖抑制作用及其对化疗药物敏感性影响的研究[J].中华耳鼻咽喉头颈外科杂志,2014,49(4):317.
[13]孙英明,谢敏,孙丽娟,等.二甲双胍调控AKT/MDR-1增强人结肠癌细胞HT-29对5-FU药物敏感性机制探讨[J].现代肿瘤医学,2015,(24):3560.
[14]Wang LW,Li ZS,Zou DW,et al.Metformin induces apoptosis of pancreatic cancer cells[J].World J Gastroenterol,2008,14(47):7192.
[15]舒婷,万福生.PI3K/Akt/mTOR信号通路与自噬及肿瘤的关系[J].中国生物化学与分子生物学报,2016,(11):1192.
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