Poly (ADP-ribose) polymerase inhibitor sensitized DNA damage caused by an alkylating pyrrole-imidazole polyamide targeting MYCN in neuroblastoma cells.

MYCN amplification (MYCN -amp) is a significant prognostic factor and early genetic marker of high-risk neuroblastoma (NB). MYCN induces the DNA damage response (DDR) and modulates the insensitivity of NB cells to Poly (ADP-ribose) polymerase (PARP) inhibitors. We previously reported that CCC-002, a DNA-alkylating agent conjugated with pyrrole-imidazole polyamide targeting MYCN , inhibits NB cell proliferation and induces DNA damage signaling. In this study, we investigated the synergistic effects of CCC-002 and PARP inhibitors on MYCN -amp NB cells. Combination treatment with PARP inhibitors significantly enhanced the sensitivity of MYCN -amp NB cells to CCC-002. DNA damage signals, such as phosphorylation of H2AX and RPA32 elicited after CCC-002 treatment, were further enhanced by PARP inhibitors, as detected through western blotting and immunofluorescence analyses. The potent cytotoxicity of this combination treatment was confirmed by the significant increase in the subG0-G1 phase. Although MYCN knockdown showed no synergistic effect with PARP inhibitors, fluorescence in situ hybridization and quantitative PCR analyses indicated that PARP inhibitors enhanced the effect of CCC-002 to reduce MYCN copy number and suppress its expression. Overall, our study provides novel insights into a therapeutic approach that combines CCC-002 and PARP inhibition to effectively induce DNA damage and apoptosis in MYCN -amp NB cells. [Display omitted] • PARP inhibitors enhance CCC-002 inhibitory effects on MYCN -amplified NB cell growth. • Copy number and expression of MYCN are reduced by the combined treatment of CCC-002 and PARP inhibitors. • CCC-002-induced DNA damage is key for PARP inhibitors' synergistic effects. • CCC-002 and PARP inhibitors cotreatment induces DNA damage and apoptosis. [ABSTRACT FROM AUTHOR]