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

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...

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Bibliographic Details
Published in:Medical sciences (Basel) 2022-05, Vol.10 (2), p.28
Main Authors: El Naggar, Olivia, Doyle, Brenna, Mariner, Kelsey, Gilmour, Susan K.
Format: Article
Language:English
Subjects:
Antibodies
Apoptosis
Biosynthesis
Cancer therapies
Chemotherapy
Cytotoxicity
difluoromethylornithine
DNA methylation
DNA repair
Enzymes
Microscopy
Mutation
Ovarian cancer
PARP inhibition
Phosphatase
Polyamines
Proteins
rucaparib
Tumors
Womens health
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Summary: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.
ISSN:2076-3271
2076-3271
DOI:10.3390/medsci10020028