Novel poly (ADP-ribose) polymerases inhibitor DHC-1 exhibits in vitro and in vivo anticancer activity on BRCA-deficient pancreatic cancer cells

Poly (ADP-ribose) polymerases (PARPs) play a key role in DNA repair. In this study we designed a novel smallmolecular 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 gamma-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.

Automated summary

The novel compound DHC-1 exhibited potent and selective inhibition of PARP-1 activity, selectively targeting BRCA1 and BRCA2-deficient cancer cells. Mechanism studies showed that DHC-1 induced DNA double-strand damage and activated apoptotic pathways in the cells. Additionally, DHC-1 enhanced the cell proliferation inhibition effect of oxaliplatin and demonstrated promising results in inhibiting tumor growth in in vivo studies, making it a potential candidate for treating BRCA-deficient pancreatic cancers.