Mechanism-informed Repurposing of Minocycline Overcomes Resistance to Topoisomerase Inhibition for Peritoneal Carcinomatosis.

ABSTRACT: 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 o

SUBMITTER: Huang HC 

PROVIDER: S-EPMC5805648 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature