Abstract
Poly (ADP-ribose) polymerases (PARPs) play a key role in DNA repair. In this study we designed a novel small-molecular compound, (E)-2-(2,3-dibromo-4,5-dimethoxybenzylidene)hydrazine-1-carbothioamide (DHC-1), which was a potent and selective PARP-1 inhibitor. DHC-1 selectively inhibited PARP-1 activity with an IC50 value of 41.12 ± 13.28 nM. Cytotoxicity results showed that DHC-1 selectively inhibited the proliferation of BRCA1-deficient breast cancer HCC-1937 and BRCA2-deficient pancreatic cancer Capan-1 cells. Mechanism studies found that DHC-1 stabilized PARP-1–DNA complexes and inhibited PAR formation in BRCA2−/− Capan-1 cells. Further experiments found that DHC-1 induced DNA double-strand damage in BRCA2−/− Capan-1 cells, which was demonstrated by accumulation of γ-H2AX foci. Flow cytometry experiments revealed that DHC-1 induced G2/M phase arrest and activate mitochondrial-induced apoptotic pathways. Interestingly, we also found that DHC-1 enhanced cell proliferation inhibitory effect of oxaliplatin (OXA). The further in vivo nude mouse studies showed that DHC-1 inhibited the growth of Capan-1 xenografts and showed a similar mechanism to that in vitro. Collectively, our results demonstrate that DHC-1 may be an excellent candidate for treatment of BRCA-deficient pancreatic cancers.
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