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

• Published in: Clinical neurology and neurosurgery 2021-08, Vol.207, p.106771-106771, Article 106771
• Main Authors: Pinheiro, Leon, Perdomo-Pantoja, Alexander, Casaos, Joshua, Huq, Sakibul, Paldor, Iddo, Vigilar, Veronica, Mangraviti, Antonella, Wang, Yuan, Witham, Timothy F., Brem, Henry, Tyler, Betty
• Format: Article
• Language: English
• Subjects: Adjuvants; Angiotensin-Converting Enzyme Inhibitors - therapeutic use; Animal models; Animals; Antibodies; Antineoplastic Agents, Alkylating - therapeutic use; Brain cancer; Brain Neoplasms - drug therapy; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain research; Captopril; Captopril - therapeutic use; Cell adhesion & migration; Cell Culture Techniques; Cell migration; Chemotherapy; Disease Models, Animal; Endopeptidases; Enzymes; Experiments; Extracellular matrix; Female; Gelatinase A; Glioma; Gliosarcoma - drug therapy; Gliosarcoma - metabolism; Gliosarcoma - pathology; Immunohistochemistry; Matrix metalloproteinase; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase-2; Medical prognosis; Metalloproteinase; Monoclonal antibodies; Rats; Rats, Inbred F344; Renin-angiotensin system; Survival; Targeted cancer therapy; Temozolomide; Temozolomide - therapeutic use; Therapeutic targets; Tumor Cells, Cultured; Tumors; Western blotting
• ISSN: 0303-8467; 1872-6968
• DOI: 10.1016/j.clineuro.2021.106771

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. 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. 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