Canagliflozin Potently Activates AMPK and Inhibits the Growth and Survival of Cancer Cells

Abstract

Many therapies that improve insulin sensitivity in type 2 diabetics activate the AMP-activated protein kinase (AMPK). Due to AMPK’s ability to inhibit protein synthesis, lipid synthesis and cell cycle progression, many studies have also investigated the role of this protein in the regulation of cancer cell growth and metabolism. Moreover, many have sought to determine whether anti-diabetic agents can influence cancer cell survival through AMPK. Canagliflozin (trade name Invokana) and dapagliflozin (trade name Forxiga) are recently approved medications for the treatment of type 2 diabetes. Both drugs display similar half-maximal inhibitory concentrations towards the sodium-dependent type 2 glucose transporter, which to date, is their only described target. Whether these drugs activate AMPK in cancer cells is not known and was therefore the focus on this study. We have found that clinically achievable concentrations of canagliflozin potently activated AMPK in lung (H1299) and prostate (PC3) cancer cells. Canagliflozin reduced mitochondrial oxygen consumption through the inhibition of complex I. These findings suggested that AMPK activation was the result of reductions in the adenylate charge of the cell. Activation of AMPK led to the inhibitory phosphorylation of acetyl-CoA carboxylase (ACC), an effect that was associated with reduced de novo lipogenesis. Canagliflozin also inhibited phosphorylation of AKT and the critical mTORC1 substrate S6 kinase. Consistent with the activation of AMPK, canagliflozin treatment inhibited lung, prostate, colon, liver, breast and ovarian cancer cell proliferation at concentrations that can be clinically achieved (20-65 μM). Low dose treatment also inhibited colony formation of lung and prostate cancer cells (IC50s 8-13 μM). These effects were potentiated when combined with the cytotoxic drug docetaxel in prostate cancer cells. In contrast, dapagliflozin was 5-10-fold less effective in all of these same assays. The results of this study therefore warrant further investigation of this approved drug for the treatment of cancers in vivo.