Clinical neurology and neurosurgery · 2021
Captopril inhibits Matrix Metalloproteinase-2 and extends survival as a temozolomide adjuvant in an intracranial gliosarcoma model.
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Pinheiro Leon, Perdomo-Pantoja Alexander, Casaos Joshua, Huq Sakibul, Paldor Iddo, Vigilar Veronica, Mangraviti Antonella, Wang Yuan, Witham Timothy F, Brem Henry, Tyler Betty
Аннотация
BACKGROUND: Captopril 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.
METHODS: Following captopril treatment, MMP-2 protein expression and migratory capabilities of 9 L gliosarcoma cells were assessed in vitro via western blots and scratch wound assays, respectively. Rats were intracranially implanted with 9 L gliosarcoma tumors, and survival was assessed in the following groups: control; captopril (30 mg/kg/day); temozolomide (TMZ) (50 mg/kg/day), and captopril+TMZ. In vivo experiments were accompanied by immunohistochemistry for MMP-2 from brain tissue.
RESULTS: In vitro, captopril decreased MMP-2 protein expression and reduced migratory capacity in 9 L 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 < 0.001), 16 (p < 0.001), and 23 (p = 0.018) days, respectively).
CONCLUSIONS: Captopril 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.
METHODS: Following captopril treatment, MMP-2 protein expression and migratory capabilities of 9 L gliosarcoma cells were assessed in vitro via western blots and scratch wound assays, respectively. Rats were intracranially implanted with 9 L gliosarcoma tumors, and survival was assessed in the following groups: control; captopril (30 mg/kg/day); temozolomide (TMZ) (50 mg/kg/day), and captopril+TMZ. In vivo experiments were accompanied by immunohistochemistry for MMP-2 from brain tissue.
RESULTS: In vitro, captopril decreased MMP-2 protein expression and reduced migratory capacity in 9 L 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 < 0.001), 16 (p < 0.001), and 23 (p = 0.018) days, respectively).
CONCLUSIONS: Captopril 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.