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.
Combined metformin-salicylate treatment provides improved anti-tumor activity and enhanced radiotherapy response in prostate cancer; drug synergy at clinically relevant doses / E.E. Tsakiridis, L. Broadfield, K. Marcinko, O.-. Biziotis, A. Ali, B. Mekhaeil, E. Ahmadi, K. Singh, A. Mesci, P.G. Zacharidis, A.E. Anagnostopoulos, T. Berg, P. Muti, G.R. Steinberg, T. Tsakiridis. - In: TRANSLATIONAL ONCOLOGY. - ISSN 1936-5233. - 14:11(2021), pp. 101209.1-101209.11. [10.1016/j.tranon.2021.101209]
|Titolo:||Combined metformin-salicylate treatment provides improved anti-tumor activity and enhanced radiotherapy response in prostate cancer; drug synergy at clinically relevant doses|
|Parole Chiave:||AMPK; HIF1a; Histone-H3; Lipogenesis; mTOR; Xenografts|
|Settore Scientifico Disciplinare:||Settore MED/03 - Genetica Medica|
|Data di pubblicazione:||2021|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.tranon.2021.101209|
|Appare nelle tipologie:||01 - Articolo su periodico|