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

Abstract

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.

• Authors: Leon Pinheiro, Alexander Perdomo-Pantoja, Joshua Casaos, Sakibul Huq, Iddo Paldor, Veronica Vigilar, Antonella Mangraviti, Yuan Wang, Timothy F Witham, Henry Brem, Betty Tyler
• Journal: Clinical neurology and neurosurgery (Clin Neurol Neurosurg) Vol. 207 Pg. 106771 (08 2021) ISSN: 1872-6968 [Electronic] Netherlands
• PMID: 34198223 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• Angiotensin-Converting Enzyme Inhibitors
• Antineoplastic Agents, Alkylating
• Captopril
• Matrix Metalloproteinase 2
• Temozolomide

Topics

• Angiotensin-Converting Enzyme Inhibitors (therapeutic use)
• Animals
• Antineoplastic Agents, Alkylating (therapeutic use)
• Brain Neoplasms (drug therapy, metabolism, pathology)
• Captopril (therapeutic use)
• Cell Culture Techniques
• Disease Models, Animal
• Female
• Gliosarcoma (drug therapy, metabolism, pathology)
• Matrix Metalloproteinase 2 (metabolism)
• Rats
• Rats, Inbred F344
• Temozolomide (therapeutic use)
• Tumor Cells, Cultured