Enhancement of the lethality of platinum-based therapy by antiprogestin mifepristone in ovarian cancer.

GAMARRA LUQUES C, TELLERIA CM

Miami, Florida - Estados Unidos

Congreso; 3rd AACR Conference on the Science of Health Disparities; 2010

American Association of Cancer Research (AACR)

The overall goal of our research is to study the feasibility of“repositioning” antiprogestin compounds originally designed for contraceptive purposes for ovarian cancer therapeutics. Ovarian cancer is the most deadly disease of the reproductive tract in women.When the disease is diagnosed, in most cases abnormal growths have already progressed beyond the confines of the ovaries and into the nearby fallopian tubes, uterus, and various other sites within the peritoneal cavity. As a result, the majority of patients diagnosed with ovarian cancer require surgery followed by platinum-based chemotherapy. Yet the efficacy of this therapy is hindered by the elevated toxicity of platinum derivatives, the development of mechanisms to evade drug toxicity, and the repopulation of cells between treatment intervals. Thus, finding therapeutic interventions to overcome the limitations of platinum-based therapies is of critical clinical relevance. Our laboratory published that the prototypical antiprogestin mifepristone has potent anti-ovarian cancer activity in vitro and in vivo; is cytostatic at pharmacological doses in platinum-sensitive and platinum-resistant ovarian cancer cells, and regardless of p53 tumor suppressor expression; and when intertwined among courses of cisplatin treatment, prevents repopulation of ovarian cancer cells.We now provide data demonstrating that mifepristone potentiates the lethality of cisplatin.We show that the toxicity of cisplatin can be enhanced ~ 4 fold when associated to cytostatic concentrations of antiprogestin mifepristone.We also demonstrate that mifepristone potentiates the long-term effect of shortterm exposure of OV2008 cells to sub-lethal doses of cisplatin. Finally we provide evidence that mifepristone enhances cisplatin toxicity in platinum sensitive OV2008 (wt p53) and A2780 (wt p53) lines, their platinum-resistant siblings, OV2008/C13 (wt p53) and A2780/CP70 (mut p53), and semi-platinum-resistant SK-OV-3 (null p53). In summary, we demonstrate that the prototypical antiprogestin mifepristone potentiates cisplatin toxicity regardless of platinum sensitivity and p53 genetic background. Our studies provide proof-of-principle that antiprogestin –of which mifepristone is FDA approved for reproductive medicine- can be“repurposed” for another modality-of-use as part of the chemotherapeutic armamentarium for ovarian cancer patients. The strategy of adding an antiprogestin such as mifepristone to the platinumbased chemotherapeutic schedule in ovarian cancer should allow reducing the number of platinum cycles or the dose of the platinum agent without losing efficacy in terms of tumor growth inhibition yet reducing undesirable side effects.