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

Justine A. Gelzinis, Melanie K. Szahaj, Roelof H. Bekendam, Sienna E. Wurl, Megan M. Pantos, Christina A. Verbetsky, Alexandre Dufresne, Meghan Shea, Kaitlind C. Howard, Oleg V. Tsodikov, Sylvie Garneau-Tsodikova, Jeffrey I. Zwicker, Daniel R. Kennedy

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article numbere22914
JournalFASEB Journal
Volume37
Issue number5
DOIs
StatePublished - May 2023

Bibliographical note

Funding Information:
The author wish to acknowledge the advice and guidance of Jennifer Ser-Dolansky and Carolanne Lovewell from the Baystate Animal Research Facility.

Funding Information:
This work was supported by a National Cancer Institute grant R21CA231000 to DRK and JIZ as well as a National Institutes of Health (NIH) F31 fellowship DEO29661 to KCH.

Publisher Copyright:
© 2023 Federation of American Societies for Experimental Biology.

Keywords

  • CA-125
  • ERP72
  • ERp5
  • ERp57
  • PDI
  • drug repurposing
  • montelukast

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Fingerprint

Dive into the research topics of 'Targeting thiol isomerase activity with zafirlukast to treat ovarian cancer from the bench to clinic'. Together they form a unique fingerprint.

Cite this