Abstract | BACKGROUND: 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.
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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 |
Journal | Translational oncology
(Transl Oncol)
Vol. 14
Issue 11
Pg. 101209
(Nov 2021)
ISSN: 1936-5233 [Print] United States |
PMID | 34479029
(Publication Type: Journal Article)
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Copyright | Copyright © 2021. Published by Elsevier Inc. |