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

• Main Authors: 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
• Format: Article
• Language: English
• Published: Elsevier 2021-11-01
• Series: Translational Oncology
• Subjects: AMPK; Lipogenesis; mTOR; HIF1a; Histone-H3; Xenografts
• Online Access: http://www.sciencedirect.com/science/article/pii/S1936523321002011

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-p70s6k/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.