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.

中文翻译：

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二甲双胍-水杨酸盐联合治疗可提高前列腺癌的抗肿瘤活性和放射治疗反应；临床相关剂量的药物协同作用

背景

需要对前列腺癌 (PrCa) 二级预防和提高对放疗 (RT) 的反应的耐受性良好的疗法。抗糖尿病药物二甲双胍 (MET) 和阿司匹林代谢物水杨酸盐 (SAL) 显示可激活 AMP 活化蛋白激酶 (AMPK)，抑制新生脂肪生成 (DNL)，即哺乳动物雷帕霉素 (mTOR) 途径的靶标，并降低 PrCa增殖在体外。本研究的目的是检查联合 MET+SAL 治疗是否可以增强 PrCa 肿瘤抑制并改善对 RT 的反应。

方法

雄激素敏感性 (22RV1) 和抗性 (PC3, DU-145) PrCa 细胞和 PC3 异种移植物用于检查与 MET+SAL 联合治疗是否可以在未辐照和辐照的 PrCa 中单独使用每种药物提供更好的抗肿瘤活性细胞和肿瘤。通过信号事件分析、线粒体呼吸和 DNL 活性测定来研究作用机制。

结果

我们观察到 PrCa 细胞对临床相关剂量的 MET 具有抗性。MET + SAL 联合治疗在临床相关剂量下提供协同抗增殖活性，并增强 RT 的抗增殖作用。这与耗氧率 (OCR) 的抑制、AMPK 的激活、乙酰辅酶 A 羧化酶 (ACC)-DNL 和 mTOR-p70 ^s6k /4EBP1 和^HIF1α通路的抑制有关。MET + SAL 减少了未受辐射肿瘤中的肿瘤生长并增强了放疗的效果。

结论

MET+SAL 治疗抑制 PrCa 细胞增殖和肿瘤生长，并在临床相关剂量下增强对放疗的反应。由于 MET 和 SAL 是安全、广泛使用且价格低廉的药物，因此这些数据支持在 PrCa 临床试验中单独和与放疗联合使用 MET+SAL 的研究。