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.