Mechanism-inspired drug repurposing that augments standard treatments offers a cost-effective and rapid route toward addressing the burgeoning problem of plateauing of effective therapeutics for drug-resistant micrometastases. We show that the antibiotic minocycline, by its ability to minimize DNA repair via reduced expression of tyrosyl-DNA phosphodiesterase-1 (Tdp1), removes a key process attenuating the efficacy of irinotecan, a frequently used chemotherapeutic against metastatic disease. Moreover, minocycline and irinotecan cooperatively mitigate each other's undesired cytokine inductions of VEGF and IL8, respectively, thereby reinforcing the benefits of each modality. These mechanistic interactions result in synergistic enhancement of irinotecan-induced platinum-resistant epithelial ovarian cancer cell death, reduced micrometastases in the omenta and mesentery by >75%, and an extended overall survival by 50% in a late-stage peritoneal carcinomatosis mouse model. Economic incentives and easy translatability make the repurposing of minocycline as a reinforcer of the topoisomerase class of chemotherapeutics extremely valuable and merits further investigations. Mol Cancer Ther; 17(2); 508–20. ©2017 AACR.

中文翻译：

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机制告知米诺环素的再利用克服了腹膜癌病对拓扑异构酶抑制的抵抗

受机制启发的药物再利用增加了标准治疗，为解决耐药性微转移有效治疗停滞这一新兴问题提供了一种具有成本效益和快速的途径。我们表明，抗生素米诺环素能够通过减少酪氨酰 DNA 磷酸二酯酶-1 (Tdp1) 的表达来最大限度地减少 DNA 修复，从而消除了减弱伊立替康疗效的关键过程，伊立替康是一种常用的针对转移性疾病的化疗药物。此外，米诺环素和伊立替康分别协同减轻彼此对 VEGF 和 IL8 的不良细胞因子诱导，从而增强了每种方式的益处。这些机械相互作用导致伊立替康诱导的铂耐药上皮卵巢癌细胞死亡的协同增强，在晚期腹膜癌病小鼠模型中，网膜和肠系膜中的微转移减少了 >75%，并将总生存期延长了 50%。经济激励和易于翻译使得将米诺环素重新用作拓扑异构酶类化学治疗剂的增强剂非常有价值，值得进一步研究。摩尔癌症治疗; 17(2); 508-20。©2017 AACR。