Multidrug resistance remains a huge challenge in the chemotherapy of cancer and numerous studies have reported that P‐glycoprotein is the most common mechanism of multidrug resistance. Verapamil has been shown to be able to reverse development of multidrug resistance mediated by P‐glycoprotein. However, the mechanism of action for verapamil in reversing multidrug resistance at the metabolic level has been rarely reported. In this research, we report the reversal effect of verapamil on multidrug resistance and its mechanisms of action using metabolomics. The results show that the P‐glycoprotein‐mediated chemotherapy drug resistance was significantly reversed by verapamil in resistant SW620/Ad300 cells. In‐depth studies demonstrated that verapamil at reversal concentration had no effect on the P‐glycoprotein expression level, but increased intramolecular accumulation of paclitaxel in SW620/Ad300 cells. Metabolomics revealed that the multidrug resistance of SW620/Ad300 cells was related to changes in glycerophospholipid metabolism, sphingolipid metabolism and citric acid cycle, and verapamil could antagonize the multidrug resistance by reversing the above‐mentioned glycerophospholipid metabolism and sphingolipid metabolism. This research shows the multidrug resistance reversal mechanism of verapamil at the metabolic level, which helps in understanding the exact multidrug resistance mechanism of verapamil and might be potentially useful to find new multidrug resistance reversal agents.

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大肠癌细胞多药耐药的代谢组学分析及维拉帕米的多药耐药逆转作用

多药耐药性仍然是癌症化学疗法中的巨大挑战，许多研究报告称P-糖蛋白是最常见的多药耐药机制。维拉帕米已被证明能够逆转由P-糖蛋白介导的多药耐药性的发展。但是，维拉帕米在代谢水平上逆转多药耐药性的作用机理鲜有报道。在这项研究中，我们报告了维拉帕米对多药耐药的逆转作用及其使用代谢组学的作用机制。结果表明，维拉帕米在耐药的SW620 / Ad300细胞中显着逆转了P-糖蛋白介导的化疗药物耐药性。深入研究表明，维拉帕米浓度逆转对P-糖蛋白表达水平没有影响，但紫杉醇在SW620 / Ad300细胞中的分子内积累增加。代谢组学研究表明，SW620 / Ad300细胞的多药耐药性与甘油磷脂代谢，鞘脂代谢和柠檬酸循环的变化有关，维拉帕米可通过逆转上述糖脂代谢和鞘脂代谢来拮抗多药耐药性。这项研究显示了维拉帕米在代谢水平上的多药耐药性逆转机制，这有助于理解维拉帕米的确切多药耐药性机制，可能对于寻找新的多药耐药性逆转剂可能有用。鞘脂代谢和柠檬酸循环，维拉帕米可以通过逆转上述甘油磷脂代谢和鞘脂代谢来拮抗多药耐药性。这项研究显示了维拉帕米在代谢水平上的多药耐药性逆转机制，这有助于了解维拉帕米的确切多药耐药性机制，并且可能对于寻找新的多药耐药性逆转剂可能有用。鞘脂代谢和柠檬酸循环，维拉帕米可以通过逆转上述甘油磷脂代谢和鞘脂代谢来拮抗多药耐药性。这项研究显示了维拉帕米在代谢水平上的多药耐药性逆转机制，这有助于理解维拉帕米的确切多药耐药性机制，可能对于寻找新的多药耐药性逆转剂可能有用。