Combined metformin-salicylate treatment provides improved anti-tumor activity and enhanced radiotherapy response in prostate cancer; drug synergy at clinically relevant doses

Evangelia E Tsakiridis; Lindsay Broadfield; Katarina Marcinko; Olga-Demetra Biziotis; Amr Ali; Bassem Mekhaeil; Elham Ahmadi; Kanwaldeep Singh; Aruz Mesci; Panayiotis G Zacharidis; Alexander E Anagnostopoulos; Tobias Berg; Paola Muti; Gregory R Steinberg; Theodoros Tsakiridis

doi:10.1016/j.tranon.2021.101209

Combined metformin-salicylate treatment provides improved anti-tumor activity and enhanced radiotherapy response in prostate cancer; drug synergy at clinically relevant doses

Transl Oncol. 2021 Nov;14(11):101209. doi: 10.1016/j.tranon.2021.101209. Epub 2021 Aug 31.

Authors

Affiliations

¹ Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
² Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada; Department of Oncology, McMaster University, Hamilton, Ontario, Canada.
³ Department of Oncology, McMaster University, Hamilton, Ontario, Canada.
⁴ Department of Radiation Oncology, Juravinski Cancer Center, 699 Concession Street, Hamilton, Ontario L8V 5C2, Canada.
⁵ Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
⁶ Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada; Department of Oncology, McMaster University, Hamilton, Ontario, Canada; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; Department of Radiation Oncology, Juravinski Cancer Center, 699 Concession Street, Hamilton, Ontario L8V 5C2, Canada. Electronic address: [email protected].

Abstract

Background: There is need for well-tolerated therapies for prostate cancer (PrCa) secondary prevention and to improve response to radiotherapy (RT). The anti-diabetic agent metformin (MET) and the aspirin metabolite salicylate (SAL) are shown to activate AMP-activated protein kinase (AMPK), suppress de novo lipogenesis (DNL), the mammalian target of rapamycin (mTOR) pathway and reduce PrCa proliferation in-vitro. The purpose of this study was to examine whether combined MET+SAL treatment could provide enhanced PrCa tumor suppression and improve response to RT.

Methods: Androgen-sensitive (22RV1) and resistant (PC3, DU-145) PrCa cells and PC3 xenografts were used to examine whether combined treatment with MET+SAL can provide improved anti-tumor activity compared to each agent alone in non-irradiated and irradiated PrCa cells and tumors. Mechanisms of action were investigated with analysis of signaling events, mitochondria respiration and DNL activity assays.

Results: We observed that PrCa cells are resistant to clinically relevant doses of MET. Combined MET + SAL treatment provides synergistic anti-proliferative activity at clinically relevant doses and enhances the anti-proliferative effects of RT. This was associated with suppression of oxygen consumption rate (OCR), activation of AMPK, suppression of acetyl-CoA carboxylase (ACC)-DNL and mTOR-p70^s6k/4EBP1 and HIF1α pathways. MET + SAL reduced tumor growth in non-irradiated tumors and enhanced the effects of RT.

Conclusion: MET+SAL treatment suppresses PrCa cell proliferation and tumor growth and enhances responses to RT at clinically relevant doses. Since MET and SAL are safe, widely-used and inexpensive agents, these data support the investigation of MET+SAL in PrCa clinical trials alone and in combination with RT.

Keywords: AMPK; HIF1a; Histone-H3; Lipogenesis; Xenografts; mTOR.