State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China; Open FIESTA Center, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China; Key Lab in Health Science and Technology, Division of Life Science and Health, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China.
Key Lab in Health Science and Technology, Division of Life Science and Health, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China.
Biochem Pharmacol. 2020 May;175:113856. doi: 10.1016/j.bcp.2020.113856. Epub 2020 Feb 14.
Cancer easily induces resistance to most chemotherapy drugs. In this study, we investigated the combination cytotoxic and antitumor effects of canagliflozin (CAN) and doxorubicin (DOX) in vitro and in vivo. CAN significantly increased the cytotoxicity of DOX in HepG2, HepG2-ADR (adriamycin or doxorubicin-resistant) and MCF7 cells. CAN significantly promoted the intracellular uptake of DOX in HepG2 cells. CAN also reduced the P-glycoprotein (P-gp) level in HepG2 cells. The function of P-gp required ATP, but CAN significantly reduced the intracellular ATP level. CAN might inhibit the function of p-gp, increase the intracellular DOX concentration and contribute to an enhanced cytotoxic activity. Autophagy plays a protective role in chemotherapy-induced cell survival. However, CAN significantly inhibited DOX-induced autophagy in HepG2 cells, and the mechanism appeared to be mediated by promoting ULK1 ser 757 phosphorylation. The downregulation of P-gp may be associated with protein degradation but is independent of the autophagy pathway. Furthermore, in HepG2-xenograft BALB/c nude mice, CAN significantly increased the antitumor effect of DOX. This study is the first to report that a classical antidiabetic drug, CAN improved the sensitivity to the antitumor effect of DOX, and the potential molecular mechanisms of CAN may involve the inhibition of P-gp function and the autophagy pathway.
癌症容易对大多数化疗药物产生耐药性。在这项研究中，我们研究了卡格列净（CAN）和阿霉素（DOX）在体外和体内联合细胞毒性和抗肿瘤作用。CAN 显著增加了 HepG2、HepG2-ADR（阿霉素或多柔比星耐药）和 MCF7 细胞中 DOX 的细胞毒性。CAN 显著促进了 HepG2 细胞中 DOX 的细胞内摄取。CAN 还降低了 HepG2 细胞中的 P 糖蛋白（P-gp）水平。P-gp 的功能需要 ATP，但 CAN 显著降低了细胞内 ATP 水平。CAN 可能抑制 p-gp 的功能，增加细胞内 DOX 浓度，并有助于增强细胞毒性活性。自噬在化疗诱导的细胞存活中起保护作用。然而，CAN 显著抑制了 HepG2 细胞中 DOX 诱导的自噬，其机制似乎是通过促进 ULK1 ser 757 磷酸化来介导的。P-gp 的下调可能与蛋白降解有关，但与自噬途径无关。此外，在 HepG2-异种移植 BALB/c 裸鼠中，CAN 显著增强了 DOX 的抗肿瘤作用。这项研究首次报道了一种经典的抗糖尿病药物，CAN 提高了对 DOX 抗肿瘤作用的敏感性，CAN 的潜在分子机制可能涉及抑制 P-gp 功能和自噬途径。
