Captopril inhibits Matrix Metalloproteinase-2 and extends survival as a temozolomide adjuvant in an intracranial gliosarcoma model

Abstract

BACKGROUND\nCaptopril is a well-characterized, FDA-approved drug that has demonstrated promise as a repurposed oncology therapeutic. Captopril s known anti-cancer effects include inhibition of Matrix Metalloproteinase-2 (MMP-2), an endopeptidase which selectively breaks down the extracellular matrix to promote cell migration. MMP-2 is a known therapeutic target in gliomas, tumors with significant clinical need. Using an aggressive gliosarcoma model, we assessed captopril s effects on MMP-2 expression in vitro and in vivo as well as its efficacy as an adjuvant in combination therapy regimens in vivo.\n\n\nMETHODS\nFollowing captopril treatment, MMP-2 protein expression and migratory capabilities of 9\xa0L gliosarcoma cells were assessed in vitro via western blots and scratch wound assays, respectively. Rats were intracranially implanted with 9\xa0L gliosarcoma tumors, and survival was assessed in the following groups: control; captopril (30\xa0mg/kg/day); temozolomide (TMZ) (50\xa0mg/kg/day), and captopril+TMZ. In vivo experiments were accompanied by immunohistochemistry for MMP-2 from brain tissue.\n\n\nRESULTS\nIn vitro, captopril decreased MMP-2 protein expression and reduced migratory capacity in 9\xa0L gliosarcoma cells. In a gliosarcoma animal model, captopril decreased MMP-2 protein expression and extended survival as a TMZ adjuvant relative to untreated controls, captopril monotherapy, and TMZ monotherapy groups (27.5 versus 14 (p\xa0<\xa00.001), 16 (p\xa0<\xa00.001), and 23 (p\xa0=\xa00.018) days, respectively).\n\n\nCONCLUSIONS\nCaptopril decreases gliosarcoma cell migration, which may be mediated by reduction in MMP-2 protein expression. Captopril provided a survival advantage as a TMZ adjuvant in a rat intracranial gliosarcoma model. Captopril may represent a promising potential adjuvant to TMZ therapy in gliosarcoma as a modulator of the MMP-2 pathway.