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

Abstract

UNLABELLED:

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 mm(3) versus 2,942 mm(3), 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-kappaB 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.

• Authors: Rosa Quiles-Perez, José Antonio Muñoz-Gámez, Angeles Ruiz-Extremera, Francisco O'Valle, Laura Sanjuán-Nuñez, Ana Belén Martín-Alvarez, David Martín-Oliva, Trinidad Caballero, Paloma Muñoz de Rueda, Josefa León, Raúl Gonzalez, Jordi Muntané, Francisco Javier Oliver, Javier Salmerón
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 51 Issue 1 Pg. 255-66 (Jan 2010) ISSN: 1527-3350 [Electronic] United States
• PMID: 20034026 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Isoquinolines
• Piperidines
• Poly(ADP-ribose) Polymerase Inhibitors
• RNA, Messenger
• 3,4-dihydro-5-(4-(1-piperidinyl)butoxy)-1(2H)-isoquinolinone
• Parp1 protein, mouse
• Poly (ADP-Ribose) Polymerase-1

Topics

• Animals
• Carcinoma, Hepatocellular (chemically induced, drug therapy, pathology)
• Gene Expression (drug effects)
• Hep G2 Cells
• Humans
• Isoquinolines (pharmacology, therapeutic use)
• Liver Neoplasms, Experimental (chemically induced, drug therapy, pathology)
• Mice
• Mice, Inbred C57BL
• Neoplasm Transplantation
• Neovascularization, Pathologic (drug therapy)
• Piperidines (pharmacology, therapeutic use)
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerase Inhibitors
• RNA, Messenger (metabolism)