Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China.
Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China.
J Pharm Biomed Anal. 2021 Jul 15;201:114129. doi: 10.1016/j.jpba.2021.114129. Epub 2021 May 7.
Doxorubicin (Dox) is commonly used for the treatment of malignant tumors, including colon cancer. However, the development of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) in tumor chemotherapy has seriously reduced the therapeutic efficacy of Dox. Natural product curcumin (Cur) was demonstrated to have a variety of pharmacological effects, such as anti-tumor, anti-oxidation and anti-aging activities. Here, we examined the MDR reversal capability of Cur in drug sensitive-(SW620) and resistant-(SW620/Ad300) colon cancer cells, and elucidated the underlying molecular mechanisms at the metabolic level. It was found that Cur reversed P-gp-mediated resistance in SW620/Ad300 cells by enhancing the Dox-induced cytotoxicity and apoptosis. Further mechanistic studies indicated that Cur inhibited the ATP-dependent transport activity of P-gp, thereby increasing the intra-celluar accumulation of Dox in drug-resistant cells. Metabolomics analysis based on UPLC-MS/MS showed that the MDR phenomenon in SW620/Ad300 cells was closely correlated with the upregulation of spermine and spermidine synthesis and D-glutamine metabolism. Cur significantly inhibited the biosynthesis of spermine and spermidine by decreasing the expression of ornithine decarboxylase (ODC) and suppressed D-glutamine metabolism, which in turn decreased the anti-oxidative stress ability and P-gp transport activity of SW620/Ad300 cells, eventually reversed MDR. These findings indicated the MDR reversal activity and the related mechanism of action of Cur, suggesting that Cur could be a promising MDR reversal agent for cancer treatment.
阿霉素（Dox）常用于治疗包括结肠癌在内的恶性肿瘤。然而，肿瘤化疗中 P-糖蛋白（P-gp）介导的多药耐药（MDR）的发展严重降低了 Dox 的治疗效果。天然产物姜黄素（Cur）被证明具有多种药理作用，如抗肿瘤、抗氧化和抗衰老活性。在这里，我们研究了 Cur 在药物敏感（SW620）和耐药（SW620/Ad300）结肠癌细胞中逆转 MDR 的能力，并在代谢水平上阐明了潜在的分子机制。结果发现，Cur 通过增强 Dox 诱导的细胞毒性和细胞凋亡，逆转了 SW620/Ad300 细胞中 P-gp 介导的耐药性。进一步的机制研究表明，Cur 抑制了 P-gp 的 ATP 依赖性转运活性，从而增加了耐药细胞内 Dox 的积累。基于 UPLC-MS/MS 的代谢组学分析表明，SW620/Ad300 细胞中的 MDR 现象与精脒和精胺合成以及 D-谷氨酰胺代谢的上调密切相关。Cur 通过降低鸟氨酸脱羧酶（ODC）的表达显著抑制精脒和精胺的生物合成，并抑制 D-谷氨酰胺代谢，从而降低 SW620/Ad300 细胞的抗氧化应激能力和 P-gp 转运活性，最终逆转 MDR。这些发现表明了 Cur 的 MDR 逆转活性及其相关作用机制，提示 Cur 可能是一种有前途的癌症治疗 MDR 逆转剂。
