Salicylate enhances the response of prostate cancer to radiotherapy

Abstract

Background Radiotherapy (RT) is a key therapeutic modality for prostate cancer (PrCa), but RT resistance necessitates dose‐escalation, often causing bladder and rectal toxicity. Aspirin, a prodrug of salicylate (SAL), has been associated with improved RT response in clinical PrCa cases, but the potential mechanism mediating this effect is unknown. SAL activates the metabolic stress sensor AMP‐activated protein kinase (AMPK), which inhibits de novo lipogenesis, and protein synthesis via inhibition of Acetyl‐CoA Carboxylase (ACC), and the mammalian Target of Rapamycin (mTOR), respectively. RT also activates AMPK through a mechanism distinctly different from SAL. Therefore, combining these two therapies may have synergistic effects on suppressing PrCa. Here, we examined the potential of SAL to enhance the response of human PrCa cells and tumors to RT. Methods Androgen‐insensitive (PC3) and ‐sensitive (LNCaP) PrCa cells were subjected to proliferation and clonogenic survival assays after treatment with clinically relevant doses of SAL and RT. Balb/c nude mice with PC3 xenografts were fed standard chow diet or chow diet supplemented with 2.5 g/kg salsalate (SAL pro‐drug dimer) one week prior to a single dose of 0 or 10 Gy RT. Immunoblotting analysis of signaling events in the DNA repair and AMPK‐mTOR pathways and lipogenesis were assessed in cells treated with SAL and RT. Results SAL inhibited proliferation and clonogenic survival in PrCa cells and enhanced the inhibition mediated by RT. Salsalate, added to diet, enhanced the anti‐tumor effects of RT in PC3 tumor xenografts. RT activated genotoxic stress markers and the activity of mTOR pathway and AMPK and mediated inhibitory phosphorylation of ACC. Interestingly, SAL enhanced the effects of RT on AMPK and ACC but blocked markers of mTOR activation. Conclusions Our results show that SAL can enhance RT responses in PrCa. Salsalate is a promising agent to investigate this concept in prospective clinical trials of PrCa 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

“…We observed that combined MET + SAL treatment has improved anti-proliferative activity in lung and prostate cancer cell lines in-vitro, compared to each agent alone [33] , but whether this therapy could be effective in-vivo alone or in combination with RT was not studied. Further, we reported the tumor suppressive efficacy of SAL and salsalate in combination with RT in PrCa models [34] , however, salsalate alone did not suppress tumor growth in non-irradiated xenografts.…”

Repurposing Drugs for Cancer Radiotherapy

“…Both findings were statistically significant, amongst the 2051 patients treated between 1981 and 2006 with a median definitive radiation dose of 76 Gy. Other preclinical 69 and clinical studies 70 have suggested that that aspirin may benefit the radiotherapy therapeutic index, which may translate to improved overall survival 70 in high-risk prostate cancer patients treated with radiotherapy. Aspirin use during preoperative chemoradiation in colorectal cancer patients may also increase tumor downstaging (67.6 % vs 43.6%, p=−.01), higher progression free survival (86.6% vs 67.1%) and overall survival (90.6% vs 73.2%), as noted in a retrospective study of 241 patients.…”