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 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).


CONCLUSIONS
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.
Quiles-Perez
Rosa
R
San Cecilio University Hospital, Granada, Spain.
Muñoz-Gámez
José Antonio
JA
Ruiz-Extremera
Angeles
A
O'Valle
Francisco
F
Sanjuán-Nuñez
Laura
L
Martín-Alvarez
Ana Belén
AB
Martín-Oliva
David
D
Caballero
Trinidad
T
Muñoz de Rueda
Paloma
P
León
Josefa
J
Gonzalez
Raúl
R
Muntané
Jordi
J
Oliver
Francisco Javier
FJ
Salmerón
Javier
J
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D015870:Gene Expression / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology* / Q000627:therapeutic use; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012333:RNA, Messenger / Q000378:metabolism
D007546:Isoquinolines; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012333:RNA, Messenger; C108729:3,4-dihydro-5-(4-(1-piperidinyl)butoxy)-1(2H)-isoquinolinone; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1