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.