The SGLT2 inhibitor canagliflozin suppresses growth and enhances prostate cancer response to radiotherapy

Amr Ali; Bassem Mekhaeil; Olga-Demetra Biziotis; Evangelia E Tsakiridis; Elham Ahmadi; Jianhan Wu; Simon Wang; Kanwaldeep Singh; Gabe Menjolian; Thomas Farrell; Aruz Mesci; Stanley Liu; Tobias Berg; Jonathan L Bramson; Gregory R Steinberg; Theodoros Tsakiridis

doi:10.1038/s42003-023-05289-w

The SGLT2 inhibitor canagliflozin suppresses growth and enhances prostate cancer response to radiotherapy

Commun Biol. 2023 Sep 8;6(1):919. doi: 10.1038/s42003-023-05289-w.

Authors

Amr Ali^{1

2

3}, Bassem Mekhaeil¹, Olga-Demetra Biziotis^{1

2

3}, Evangelia E Tsakiridis^{2

4}, Elham Ahmadi^{1

2}, Jianhan Wu^{2

4}, Simon Wang^{1

2

3}, Kanwaldeep Singh^{1

3}, Gabe Menjolian⁵, Thomas Farrell⁶, Aruz Mesci^{1

7}, Stanley Liu⁸, Tobias Berg^{1

3}, Jonathan L Bramson^{1

3

9}, Gregory R Steinberg^{2

4

10}, Theodoros Tsakiridis^{11

12

13

14

15}

Affiliations

¹ Departments of Oncology, McMaster University, Hamilton, ON, Canada.
² Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada.
³ Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada.
⁴ Departments of Medicine, McMaster University, Hamilton, ON, Canada.
⁵ Department of Radiotherapy, Juravinski Cancer Center, Hamilton, ON, Canada.
⁶ Department of Physics, Juravinski Cancer Center, Hamilton, Ontario, Canada.
⁷ Department of Radiation Oncology, Juravinski Cancer Center, Hamilton, ON, Canada.
⁸ Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.
⁹ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
¹⁰ Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
¹¹ Departments of Oncology, McMaster University, Hamilton, ON, Canada. tsakirt@mcmaster.ca.
¹² Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada. tsakirt@mcmaster.ca.
¹³ Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada. tsakirt@mcmaster.ca.
¹⁴ Department of Radiation Oncology, Juravinski Cancer Center, Hamilton, ON, Canada. tsakirt@mcmaster.ca.
¹⁵ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada. tsakirt@mcmaster.ca.

Abstract

Radiotherapy is a non-invasive standard treatment for prostate cancer (PC). However, PC develops radio-resistance, highlighting a need for agents to improve radiotherapy response. Canagliflozin, an inhibitor of sodium-glucose co-transporter-2, is approved for use in diabetes and heart failure, but is also shown to inhibit PC growth. However, whether canagliflozin can improve radiotherapy response in PC remains unknown. Here, we show that well-tolerated doses of canagliflozin suppress proliferation and survival of androgen-sensitive and insensitive human PC cells and tumors and sensitize them to radiotherapy. Canagliflozin blocks mitochondrial respiration, promotes AMPK activity, inhibits the MAPK and mTOR-p70^S6k/4EBP1 pathways, activates cell cycle checkpoints, and inhibits proliferation in part through HIF-1α suppression. Canagliflozin mediates transcriptional reprogramming of several metabolic and survival pathways known to be regulated by ETS and E2F family transcription factors. Genes downregulated by canagliflozin are associated with poor PC prognosis. This study lays the groundwork for clinical investigation of canagliflozin in PC prevention and treatment in combination with radiotherapy.

Publication types

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

MeSH terms

Canagliflozin / pharmacology
Canagliflozin / therapeutic use
Heart Failure*
Humans
Male
Mitochondria
Prostatic Neoplasms* / drug therapy
Prostatic Neoplasms* / radiotherapy
Sodium-Glucose Transporter 2 Inhibitors* / pharmacology

Substances

Canagliflozin
Sodium-Glucose Transporter 2 Inhibitors

Grants and funding

CIHR/Canada