Inhibition of poly adenosine diphosphate‐ribose polymerase decreases hepatocellular carcinoma growth by modulation of tumor‐related gene expression

Hepatocellular carcinoma (HCC) is associated with a poor prognosis due to a lack of effective treatment options. In HCC a significant role is played by DNA damage and the inflammatory response. Poly (ADP‐ribose) polymerase‐1 (PARP‐1) is an important protein that regulates both these mechanisms. The objective of this study was to examine the effect of pharmacology PARP‐1 inhibition on the reduction of tumor volume of HCC xenograft and on the hepatocarcinogenesis induced by diethyl‐nitrosamine (DEN). Pharmacologic PARP‐1 inhibition with DPQ greatly reduces tumor xenograft volume with regard to a nontreated xenograft (394 mm3 versus 2,942 mm3, P < 0.05). This observation was paralleled by reductions in xenograft mitosis (P = 0.02) and tumor vasculogenesis (P = 0.007, confirmed by in vitro angiogenesis study), as well as by an increase in the number of apoptotic cells in DPQ‐treated mice (P = 0.04). A substantial difference in key tumor‐related gene expression (transformed 3T3 cell double minute 2 [MDM2], FLT1 [vascular endothelial growth factor receptor‐1, VEGFR1], epidermal growth factor receptor [EPAS1]/hypoxia‐inducible factor 2 [HIF2A], EGLN1 [PHD2], epidermal growth factor receptor [EGFR], MYC, JUND, SPP1 [OPN], hepatocyte growth factor [HGF]) was found between the control tumor xenografts and the PARP inhibitor‐treated xenografts (data confirmed in HCC cell lines using PARP inhibitors and PARP‐1 small interfering RNA [siRNA]). Furthermore, the results obtained in mice treated with DEN to induce hepatocarcinogenesis showed, after treatment with a PARP inhibitor (DPQ), a significant reduction both in preneoplastic foci and in the expression of preneoplastic markers and proinflammatory genes (Gstm3, Vegf, Spp1 [Opn], IL6, IL1b, and Tnf), bromodeoxyuridine incorporation, and NF‐κB activation in the initial steps of carcinogenesis (P < 0.05). Conclusion: This study shows that PARP inhibition is capable of controlling HCC growth and preventing tumor vasculogenesis by regulating the activation of different genes involved in tumor progression. (HEPATOLOGY 2010;51:255–266.)