Metformin Synergistically Potentiates the Antitumor Effects of Imatinib in Colorectal Cancer Cells.
Metformin Synergistically Potentiates the Antitumor Effects of Imatinib in Colorectal Cancer Cells.
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DOI：
10.12717/dr.2017.21.2.139
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发表时间：
2017-06
期刊：
影响因子：
--
通讯作者：
Lee Y
中科院分区：
文献类型：
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作者：
Lee J;Park D;Lee Y
二甲双胍是最常用的抗糖尿病药物，副作用相对较小。大量证据表明，二甲双胍与降低癌症风险和对多种癌细胞的抗癌活性相关。酪氨酸激酶抑制剂伊马替尼已显示出治疗慢性髓性白血病的强大活性，并且还诱导结直肠癌细胞的生长停滞和凋亡。在这项研究中，我们测试了伊马替尼和二甲双胍对HCT 15结直肠癌细胞的组合对细胞活力，细胞周期和自噬的影响。我们的数据表明，二甲双胍协同增强伊马替尼在HCT 15细胞中的细胞毒性，如联合和药物减少指数所示。我们还证明，该组合导致协同下调pERK，细胞周期阻滞在S期和G2/M期通过减少细胞周期蛋白B1水平。此外，该组合导致自噬诱导，如通过增加的酸性囊泡细胞器和裂解形式的LC 3-II所揭示的。氯喹抑制自噬过程导致细胞活力降低，表明诱导自噬似乎起细胞保护作用，可能对抗癌作用。总之，我们目前的数据表明，二甲双胍联合伊马替尼可能是一个有前途的治疗选择结直肠癌。
Metformin is the most commonly prescribed anti-diabetic drug with relatively minor side effect. Substantial evidence has suggested that metformin is associated with decreased cancer risk and anticancer activity against diverse cancer cells. The tyrosine kinase inhibitor imatinib has shown powerful activity for treatment of chronic myeloid leukemia and also induces growth arrest and apoptosis in colorectal cancer cells. In this study, we tested the combination of imatinib and metformin against HCT15 colorectal cancer cells for effects on cell viability, cell cycle and autophagy. Our data show that metformin synergistically enhances the imatinib cytotoxicity in HCT15 cells as indicated by combination and drug reduction indices. We also demonstrate that the combination causes synergistic down-regulation of pERK, cell cycle arrest in S and G2/M phases via reduction of cyclin B1 level. Moreover, the combination resulted in autophagy induction as revealed by increased acidic vesicular organelles and cleaved form of LC3-II. Inhibition of autophagic process by chloroquine led to decreased cell viability, suggesting that induction of autophagy seems to play a cell protective role that may act against anticancer effects. In conclusion, our present data suggest that metformin in combination with imatinib might be a promising therapeutic option in colorectal cancer.