Targeting thiol isomerase activity with zafirlukast to treat ovarian cancer from the bench to clinic

Gelzinis, J. A., Szahaj, M. K., Bekendam, R. H., Wurl, S. E., Pantos, M. M., Verbetsky, C. A., Dufresne, A., Shea, M., Howard, K. C., Tsodikov, O. V., Garneau‐Tsodikova, S., Zwicker, J. I. and Kennedy, D. R. ORCID: https://orcid.org/0000-0002-4359-6911 (2023) Targeting thiol isomerase activity with zafirlukast to treat ovarian cancer from the bench to clinic. The FASEB Journal, 37 (5). e22914. ISSN 1530-6860 doi: 10.1096/fj.202201952r

Abstract/Summary

Thiol isomerases, including PDI, ERp57, ERp5, and ERp72, play important and distinct roles in cancer progression, cancer cell signaling, and metastasis. We recently discovered that zafirlukast, an FDA-approved medication for asthma, is a pan-thiol isomerase inhibitor. Zafirlukast inhibited the growth of multiple cancer cell lines with an IC50 in the low micromolar range, while also inhibiting cellular thiol isomerase activity, EGFR activation, and downstream phosphorylation of Gab1. Zafirlukast also blocked the procoagulant activity of OVCAR8 cells by inhibiting tissue factor-dependent Factor Xa generation. In an ovarian cancer xenograft model, statistically significant differences in tumor size between control vs treated groups were observed by Day 18. Zafirlukast also significantly reduced the number and size of metastatic tumors found within the lungs of the mock-treated controls. When added to a chemotherapeutic regimen, zafirlukast significantly reduced growth, by 38% compared with the mice receiving only the chemotherapeutic treatment, and by 83% over untreated controls. Finally, we conducted a pilot clinical trial in women with tumor marker-only (CA-125) relapsed ovarian cancer, where the rate of rise of CA-125 was significantly reduced following treatment with zafirlukast, while no severe adverse events were reported. Thiol isomerase inhibition with zafirlukast represents a novel, well-tolerated therapeutic in the treatment of ovarian cancer.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/111676
Identification Number/DOI	10.1096/fj.202201952r
Refereed	Yes
Divisions	Interdisciplinary centres and themes > Institute for Cardiovascular and Metabolic Research (ICMR)
Uncontrolled Keywords	Genetics, Molecular Biology, Biochemistry, Biotechnology
Publisher	Wiley
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