Dual Roles of Canagliflozin on Cholangiocarcinoma Cell Growth and Enhanced Growth Suppression in Combination with FK866.

Cholangiocarcinoma-associated mortality has been increasing over the past decade. The sodium-glucose cotransporter 2 inhibitor, canagliflozin, has demonstrated anti-tumor effects against several types of cancers; however, studies examining its potential impact on cholangiocarcinoma are lacking. This study investigated the anti-tumor effects of canagliflozin on cholangiocarcinoma and the effects of nicotinamide adenine dinucleotide (NAD)+ salvage pathway activation and sirtuin 1 on tumor growth. We evaluated cell proliferation and gene expression in several cholangiocarcinoma cell lines and analyzed the effects of canagliflozin on cell proliferation, apoptosis, and migration. Canagliflozin treatment decreased the viability of cholangiocarcinoma cells in a concentration-dependent manner but increased the viability at low concentrations in several cell lines. At high concentrations, canagliflozin arrested the cell cycle checkpoint in the G0/G1 phase. In contrast, at low concentrations, it increased the proportion of cells in the S phase. Canagliflozin also reduced the migratory ability of cholangiocarcinoma cells in a concentration-dependent manner. Canagliflozin treatment upregulated nicotinamide phosphoribosyltransferase (NAMPT), NAD+, and sirtuin 1 in cholangiocarcinoma and activated the NAD+ salvage pathway. The growth-inhibitory effect of canagliflozin was enhanced when combined with an NAMPT inhibitor. Canagliflozin inhibits cholangiocarcinoma cell growth and migration and its anti-tumor effect is enhanced when combined with an NAMPT inhibitor. However, further investigation is required because of its potential tumor growth-promoting effect through the activation of the NAD+ salvage pathway.