Metformin attenuates hypoxia-induced resistance to cisplatin in the HepG2 cell line
Metformin attenuates hypoxia-induced resistance to cisplatin in the HepG2 cell line
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DOI：
10.3892/ol.2018.9869
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发表时间：
2019-02-01
期刊：
影响因子：
2.9
通讯作者：
Takai, Yoshihiro
中科院分区：
文献类型：
--
作者：
Fujita, Hiromasa;Hirose, Katsumi;Takai, Yoshihiro
肝母细胞瘤是儿童最常见的肝脏肿瘤。术前化疗和手术改善了治疗结果；然而，在晚期病例的治疗方面还需要进一步改进。近年来，经动脉化疗栓塞术(TACE)的疗效受到人们的重视。TACE通过经导管给予抗肿瘤药物来增加局部药物浓度，并通过栓塞供血动脉来诱导肿瘤坏死。然而，研究表明，肿瘤在低氧环境下对抗癌药物表现出抗药性。二甲双胍是一种用于治疗2型糖尿病的药物；然而，最近的报告表明，它也可能在各种癌细胞株中显示出抗肿瘤作用。这些效应被认为是通过激活一磷酸腺苷活化的蛋白激酶和减少哺乳动物雷帕霉素信号的靶点来实现的，但这些效应发生在不适合临床使用的高浓度环境中。在生理浓度增加的情况下，二甲双胍的潜在疗效尚未得到评估。本研究探讨了低浓度二甲双胍联合顺铂在低氧条件下对肝癌细胞株HepG2的治疗作用。将HepG2细胞单独用顺铂、二甲双胍或两种药物联合作用，在常氧或低氧条件下培养。在低氧条件下，单独使用5 mU M顺铂或1 mM二甲双胍并不显著影响细胞的增殖或凋亡。而当5 mU M顺铂与1 mM二甲双胍联合应用时，可显著抑制低氧条件下的细胞增殖和诱导细胞凋亡。综上所述，低浓度的二甲双胍可减轻低氧诱导的HepG2细胞对顺铂的耐药性。选择性地将有效剂量的二甲双胍输送到肝母细胞瘤可能是可以实现的，并且在临床上是有用的。
Hepatoblastoma is the most commonly occurring liver tumor in children. Preoperative chemotherapy and surgery have improved treatment outcomes; however, further improvements are required in the treatment of advanced cases. Recently, the efficacy of transarterial chemoembolization (TACE) has garnered attention. TACE increases the local concentration of drugs by transcatheterically administering antitumor agents, and induces necrosis in the tumor by embolizing the feeding artery. However, studies have revealed that tumors exhibit resistance to anticancer drugs in hypoxic environments. Metformin is a drug used to treat type 2 diabetes; however, recent reports have indicated that it may also exhibit antitumor effects in various cancer cell lines. These effects are hypothesized to be mediated by the activation of adenosine monophosphate-activated protein kinase and reduction of mammalian target of rapamycin signaling, but these effects occur at high concentrations that are not suitable for use in a clinical setting. The potential efficacy of metformin at increased physiological concentrations has not been evaluated. The present study investigated the therapeutic effect of low concentrations of metformin in combination with cisplatin on liver cancer HepG2 cells in hypoxic conditions. HepG2 cells were treated with cisplatin alone, metformin alone, or a combination of these two drugs and cultured in normoxia or hypoxia. Treatment with either 5 mu M cisplatin or 1 mM metformin alone did not significantly affect cell proliferation or apoptosis in hypoxic conditions. However, when 5 mu M cisplatin was combined with 1 mM metformin, a significant inhibition of cell proliferation and induction of apoptosis was observed in hypoxic HepG2 cells. In conclusion, a low concentration of metformin attenuates hypoxia-induced resistance to cisplatin in HepG2 cells. Selective delivery of an effective dose of metformin to a hepatoblastoma tumor may be achievable and clinically useful with TACE.