Mechanism-informed Repurposing of Minocycline Overcomes Resistance to Topoisomerase Inhibition for Peritoneal Carcinomatosis.
Mechanism-informed Repurposing of Minocycline Overcomes Resistance to Topoisomerase Inhibition for Peritoneal Carcinomatosis.
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DOI：
10.1158/1535-7163.mct-17-0568
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发表时间：
2018-03
影响因子：
5.7
通讯作者：
Hasan T
中科院分区：
文献类型：
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作者：
Huang HC;Liu J;Baglo Y;Rizvi I;Anbil S;Pigula M;Hasan T
机制启发的药物再利用增加了标准治疗，为解决耐药微转移有效治疗的平台化问题提供了一种具有成本效益和快速的途径。我们发现抗生素二甲胺四环素能够通过降低酪氨酸-DNA磷酸二酯酶-1 （Tdp1）的表达来最小化DNA修复，从而消除了削弱伊立替康（一种常用的用于转移性疾病的化疗药物）疗效的关键过程。此外，米诺环素和伊立替康分别协同减轻了彼此对VEGF和IL-8的不良细胞因子诱导，从而增强了每种方式的益处。在一个晚期腹膜癌小鼠模型中，这些机制的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，网膜和肠系膜微转移减少了75%，总生存期延长了50%。经济激励和易于翻译使得二甲胺四环素作为拓扑异构酶类化疗药物的强化剂的再利用非常有价值，值得进一步研究。
Mechanism-inspired drug repurposing that augments standard treatments offers a cost-effective and a 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 IL-8 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.