Difluoromethylornithine (DFMO) Enhances the Cytotoxicity of PARP Inhibition in Ovarian Cancer Cells

Abstract

Ovarian cancer accounts for 3% of the total cancers in women, yet it is the fifth leading cause of cancer deaths among women. The BRCA1/2 germline and somatic mutations confer a deficiency of the homologous recombination (HR) repair pathway. Inhibitors of poly (ADP-ribose) polymerase (PARP), another important component of DNA damage repair, are somewhat effective in BRCA1/2 mutant tumors. However, ovarian cancers often reacquire functional BRCA and develop resistance to PARP inhibitors. Polyamines have been reported to facilitate the DNA damage repair functions of PARP. Given the elevated levels of polyamines in tumors, we hypothesized that treatment with the polyamine synthesis inhibitor, α-difluoromethylornithine (DFMO), may enhance ovarian tumor sensitivity to the PARP inhibitor, rucaparib. In HR-competent ovarian cancer cell lines with varying sensitivities to rucaparib, we show that co-treatment with DFMO increases the sensitivity of ovarian cancer cells to rucaparib. Immunofluorescence assays demonstrated that, in the presence of hydrogen peroxide-induced DNA damage, DFMO strongly inhibits PARylation, increases DNA damage accumulation, and reduces cell viability in both HR-competent and deficient cell lines. In vitro viability assays show that DFMO and rucaparib cotreatment significantly enhances the cytotoxicity of the chemotherapeutic agent, cisplatin. These results suggest that DFMO may be a useful adjunct chemotherapeutic to improve the anti-tumor efficacy of PARP inhibitors in treating ovarian cancer.

Polyamines in Ovarian Aging and Disease

“…Simultaneous exposure of ovarian cancer cells to DFMO and rucaparib (PARP inhibitor) inhibited polyamine synthesis and PARP activity, thereby enhancing the killing effect of cisplatin on ovarian cancer cells. These findings suggest that DFMO can be used as an adjuvant chemotherapeutic agent in the treatment of ovarian cancer [89].…”

Editorial to the Special Issue on “Polyamine Metabolism in Health and Disease: Potential for Polyamine-Targeted Therapies and Prevention”

“…DFMO acts as a suicide inhibitor of the first rate-limiting enzyme in polyamine biosynthesis, ornithine decarboxylase (ODC), thereby limiting intracellular polyamine concentrations. In a research article by El Naggar and colleagues [ 7 ], DFMO is demonstrated to improve the response of ovarian cancer cells to the PARP inhibitor rucaparib by increasing chemotherapy-mediated DNA damage. Considering the well-established clinical safety profile of DFMO, the inclusion of polyamine-blocking therapy as an adjunct to chemotherapy in ovarian cancer should be considered.…”