Biomed Chromatogr. 2020 Aug 27:e4976. doi: 10.1002/bmc.4976. Online ahead of print.
Multidrug resistance remained a huge challenge in the chemotherapy of cancer and numerous studies reported that P-glycoprotein is the most common mechanism of multidrug resistance. Verapamil has been shown to be able to reverse development of the multidrug resistance mediated by P-glycoprotein. However, the mechanism of action for verapamil to reverse the multidrug resistance at the metabolic level has been rarely reported. In this research, we report the reversal effect of verapamil on the
multidrug resistance and its mechanisms of action using metabolomics. The results showed that the P-glycoprotein-mediated chemotherapy drug resistance was significantly reversed by verapamil in resistant SW620/Ad300 cells. In-depth studies demonstrated 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 abovementioned glycerophospholipid metabolism and sphingolipid metabolism. This research represents the multidrug resistance reversal mechanism of verapamil at the metabolic level, which helps to understand the exact multidrug resistance mechanism of verapamil and might be potentially used to find new multidrug resistance reversal agents.