The Diabetes Drug Canagliflozin Enhances the Response of Prostate Cancer to Radiotherapy

Abstract

Canagliflozin (CANA) is a sodium-glucose co-transporter 2 (SGLT2) inhibitor used for the treatment of type II diabetes. There is recent evidence suggesting that Canagliflozin has antiproliferative effects against malignant tumours. Canagliflozin is able to inhibit cell growth and cancer progression by inhibiting mitochondrial complex I leading to a reduction in cellular ATP levels. This alteration in the energy status of the cell leads to AMP-activated kinase (AMPK) activation, which in turn downregulates protein synthesis, lipogenesis and induces cell cycle arrest. The aim of this thesis is to explore whether Canagliflozin can be combined with radiation to enhance the outcome of radiation therapy in the treatment of prostate cancer and to further our knowledge on the cellular pathways impacted by Canagliflozin. Proliferation and clonogenic survival assays were used to establish the antiproliferative effect of Canagliflozin in vitro alone and when combined with radiation. Prostate cancer cell lines with different mutation profiles were used to assess the effectiveness of the drug under different radiation doses. A xenograft model was then used to test Canagliflozin’s effects in vivo. PC-3 cells were injected in the flank of balb/c nude mice. Mice were treated with Canagliflozin, radiation or a combined treatment and tumour growth was monitored. Furthermore, a western blot analysis of cells treated with Canagliflozin and radiation was performed to deepen our understanding of the cellular pathways affected by Canagliflozin. Our results show that Canagliflozin has an additive effect when combined with radiation. Canagliflozin was able to effectively downregulate the mTOR pathway, blocking mitosis and leading to cell cycle arrest. These findings provide evidence that Canagliflozin could be used as an adjunct to radiation therapy in clinical settings.