Despite significant advances in combinations of radiotherapy and chemotherapy, altered fractionation schedules and image-guided radiotherapy, many cancer patients fail to benefit from radiation. A prevailing hypothesis is that targeting repair of DNA double strand breaks (DSB) can enhance radiation effects in the tumor and overcome therapeutic resistance without incurring off-target toxicities. Unrepaired DSBs can block cancer cell proliferation, promote cancer cell death, and induce cellular senescence. Given the slow progress to date translating novel DSB repair inhibitors as radiosensitizers, we have explored drug repurposing, a proven route to improving speed, costs, and success rates of drug development. In a prior screen where we tracked resolution of ionizing radiation-induced foci (IRIF) as a proxy for DSB repair, we had identified pitavastatin (Livalo), an HMG-CoA reductase inhibitor commonly used for lipid lowering, as a candidate radiosensitizer. Here, we report that pitavastatin and other lipophilic statins are potent inhibitors of DSB repair in breast and melanoma models both in vitro and in vivo. When combined with ionizing radiation, pitavastatin increased persistent DSBs, induced senescence, and enhanced acute effects of radiation on radioresistant melanoma tumors. shRNA knockdown implicated HMG-CoA reductase, farnesyl diphosphate synthase, and protein farnesyl transferase in IRIF resolution, DSB repair, and senescence. These data confirm on-target activity of statins, although via inhibition of protein prenylation rather than cholesterol biosynthesis. In light of prior studies demonstrating enhanced efficacy of radiotherapy in patients taking statins, this work argues for clinical evaluation of lipophilic statins as nontoxic radiosensitizers to enhance the benefits of image-guided radiotherapy. Mol Cancer Ther; 17(2); 407–18. ©2017 AACR. See all articles in this MCT Focus section, “Developmental Therapeutics in Radiation Oncology.”

中文翻译：

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HMG-CoA 还原酶抑制延迟 DNA 修复并促进肿瘤照射后的衰老

尽管在放疗和化疗的组合、改变的分割计划和图像引导放疗方面取得了重大进展，但许多癌症患者未能从放疗中受益。一个普遍的假设是靶向修复 DNA 双链断裂 (DSB) 可以增强肿瘤中的辐射效应并克服治疗耐药性，而不会引起脱靶毒性。未修复的 DSBs 可以阻断癌细胞增殖，促进癌细胞死亡，并诱导细胞衰老。鉴于迄今为止将新型 DSB 修复抑制剂转化为放射增敏剂的进展缓慢，我们探索了药物再利用，这是提高药物开发速度、成本和成功率的行之有效的途径。在之前的屏幕中，我们跟踪了电离辐射诱发灶 (IRIF) 的分辨率作为 DSB 修复的代理，我们已将匹伐他汀 (Livalo)（一种常用于降脂的 HMG-CoA 还原酶抑制剂）确定为候选放射增敏剂。在这里，我们报告说匹伐他汀和其他亲脂性他汀类药物是体外和体内乳腺和黑色素瘤模型中 DSB 修复的有效抑制剂。当与电离辐射相结合时，匹伐他汀增加了持久性 DSB，诱导衰老，并增强了辐射对抗辐射黑色素瘤肿瘤的急性影响。shRNA 敲低涉及 HMG-CoA 还原酶、法呢基二磷酸合酶和蛋白质法呢基转移酶在 IRIF 分辨率、DSB 修复和衰老中。这些数据证实了他汀类药物的靶向活性，尽管是通过抑制蛋白质异戊二烯化而不是胆固醇生物合成。鉴于先前的研究表明放射治疗对服用他汀类药物的患者具有增强的疗效，这项工作主张将亲脂性他汀类药物作为无毒放射增敏剂进行临床评估，以提高图像引导放射治疗的益处。摩尔癌症治疗; 17(2); 407-18。©2017 AACR。请参阅此 MCT 焦点部分中的所有文章，“放射肿瘤学中的发育疗法”。