Canagliflozin inhibits p-gp function and early autophagy and improves the sensitivity to the antitumor effect of doxorubicin

Jin Zhong; Pengbo Sun; Naihan Xu; Meijian Liao; Chenke Xu; Yipei Ding; Jin Cai; Yaou Zhang; Weidong Xie

doi:10.1016/j.bcp.2020.113856

Canagliflozin inhibits p-gp function and early autophagy and improves the sensitivity to the antitumor effect of doxorubicin

Biochem Pharmacol. 2020 May:175:113856. doi: 10.1016/j.bcp.2020.113856. Epub 2020 Feb 14.

Authors

Jin Zhong¹, Pengbo Sun¹, Naihan Xu¹, Meijian Liao², Chenke Xu², Yipei Ding³, Jin Cai⁴, Yaou Zhang⁵, Weidong Xie⁶

Affiliations

¹ 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.
² Key Lab in Health Science and Technology, Division of Life Science and Health, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China.
³ State Key Laboratory of Chemical Oncogenomics, 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.
⁴ 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.
⁵ 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. Electronic address: zhangyo@sz.tsinghua.edu.cn.
⁶ 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. Electronic address: xiewd@sz.tsinghua.edu.cn.

PMID: 32061772
DOI: 10.1016/j.bcp.2020.113856

Abstract

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.

Keywords: Autophagy; Canagliflozin; Doxorubicin; Drug resistance; P-glycoprotein.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
Adenosine Triphosphate / metabolism
Animals
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology*
Autophagy / drug effects*
Canagliflozin / pharmacology*
Cell Culture Techniques
Cell Survival / drug effects
Doxorubicin / metabolism
Doxorubicin / pharmacology*
Drug Resistance, Neoplasm / drug effects*
Drug Synergism
Hep G2 Cells
Humans
MCF-7 Cells
Mice, Inbred BALB C
Mice, Nude
Xenograft Model Antitumor Assays

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
Antineoplastic Agents
Canagliflozin
Doxorubicin
Adenosine Triphosphate