Mifepristone inhibits non-small cell lung carcinoma cellular escape from DNA damaging cisplatin

Lung cancer is the leading cause of cancer deaths in the world. The major histopathological subtype of lung cancer is non-small cell lung cancer (NSCLC). Platinum-based therapy is the standard of care for patients with advanced stage NSCLC. However, even with treatment, most patients will die of this disease within 5 years and most of these deaths are due to recurrence. One strategy to inhibit recurrence is to use cytostatic compounds following courses of lethal chemotherapy. We have shown in various cancer cell types that mifepristone (MF), an anti-progestin/anti-glucocorticoid, is a powerful cytostatic anti-cancer agent. Thus, in this work we tested the hypothesis that MF should be efficacious in inducing cytostasis and preventing repopulation of NSCLC following cisplatin (CDDP) therapy.

We established an in vitro approach wherein human NSCLC cells with different genetic backgrounds and sensitivities to CDDP (A549 and H23) were exposed to rounds of lethal concentrations of CDDP for 1 h followed or not by MF monotherapy. Every 2 days, cell number, cell viability, and colony-forming ability of viable cells were studied.

CDDP killed the majority of cells, yet there were remnant cells escaping CDDP lethality and repopulating the culture, as evidenced by the improved clonogenic survival of viable cells. In contrast, when cells exposed to CDDP where further treated with MF following CDDP removal, their number and clonogenic capacity were reduced drastically.

This study reports that there is repopulation of NSCLC cells following a lethal concentration of CDDP monotherapy, that NSCLC cells are sensitive to the growth inhibition properties of MF, and that MF abrogates the repopulation of NSCLC cells following CDDP therapy. Our study supports further evaluating MF as an adjuvant therapy for NSCLC.