Yang Xiaofan, Ding Yufeng, Xiao Miao, Liu Xin, Ruan Jinlan, Xue Pingping
Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Chem Biol Interact. 2017 Dec 25;278:22-31. doi: 10.1016/j.cbi.2017.10.008. Epub 2017 Oct 5.
RY10-4, an anti-tumor agent, exerts cytotoxicity to various human cancer cell lines. However, few studies reported the effect of combined application of RY10-4 and chemotherapeutic drugs against cancer cells with multidrug resistance (MDR). In this study, P-glycoprotein (P-gp), which is reported to mediate MDR to anti-cancer drugs, was proved to be overexpressed in the adriamycin (ADR)-resistant human breast cancer cells, namely MCF-7/ADR cells. Furthermore, RY10-4 application resulted in a downregulation of P-gp in MCF-7/ADR cells, thus leading to higher chemosensitivity to ADR. Our study further demonstrated that the MDR phenomenon was under the control of the PI3K/Akt/NF-κB pathway, which was suppressed by RY10-4, leading to MDR reversal effects in MCF-7/ADR cells. In vivo, MCF-7/ADR cells were effectively suppressed by the combined ADR/RY10-4 treatment compared with the ADR-alone treatment. Taken together, these results demonstrated that RY10-4 reverses the MDR phenotype in MCF-7/ADR cells by suppressing the PI3K/Akt/NF-κB pathway.
抗肿瘤药物 RY10-4 对多种人类癌细胞系具有细胞毒性。然而，很少有研究报道 RY10-4 与化疗药物联合应用对多药耐药（MDR）癌细胞的影响。在本研究中，据报道介导对抗癌药物产生 MDR 的 P-糖蛋白（P-gp）在阿霉素（ADR）耐药的人乳腺癌细胞即 MCF-7/ADR 细胞中被证明过度表达。此外，应用 RY10-4 导致 MCF-7/ADR 细胞中 P-gp 下调，从而导致对 ADR 的化疗敏感性更高。我们的研究进一步表明，MDR 现象受 PI3K/Akt/NF-κB 信号通路调控，而该信号通路被 RY10-4 抑制，从而在 MCF-7/ADR 细胞中产生 MDR 逆转效应。在体内，与单独使用 ADR 治疗相比，联合使用 ADR/RY10-4 治疗可有效抑制 MCF-7/ADR 细胞。综上所述，这些结果表明 RY10-4 通过抑制 PI3K/Akt/NF-κB 信号通路逆转 MCF-7/ADR 细胞中的 MDR 表型。
