Cell-cycle inhibition by TNP-470 in an in vivo model of hepatocarcinoma is mediated by a p53 and p21WAF1/CIP1 mechanism.
The objective of this study was to determine in a rat model of hepatocellular carcinoma (HCC) the effects of the antiangiogenic agent TNP-470 on cell proliferation and effectors of the apoptotic pathway, including p53, p21WAF1/CIP1, cyclin D, and cyclin E. Tumor was induced in male Wistar rats by diethylnitrosamine and promoted by two-thirds hepatectomy plus acetaminofluorene administration. Experiments were carried out at 28 weeks after initiating the treatment. TNP-470 was administered at 30 mg/kg, 3 times per week from 20 to 28 weeks. Serum levels of vascular endothelial growth factor (VEGF) and hepatocyte growth factor beta (HGFbeta) liver expression were increased by hepatocarcinogenesis (+38% and +183%, respectively), and treatment with TNP-470 was able to prevent the increase in these angiogenic factors induced by HCC. HCC coursed with reduced expression of p21WAF1/CIP1 and p53 (-63% and -60%, respectively). Hepatic expression of cyclin D and cyclin E were significantly increased in rats with HCC (+108% and +115%, respectively). In animals with experimental carcinogenesis, a significant increase in the expression of Cdk4 and CdK2 was also observed (+119% and +187%, respectively). These effects were prevented by TNP-470 administration. In conclusion, cell-cycle inhibition by TNP-470 is mediated at least in part by an activation of p21WAF1/CIP1 because of a p53-dependent mechanism, with reduction of the cyclin D-Cdk4 and cyclin E-Cdk 2 expression. These cytostatic effects should be considered when assessing the efficacy of TNP-470 for anti-angiogenic therapy. These findings may prove useful for the development of therapies for the treatment of human HCC.
Mauriz
José L
JL
Department of Physiology, University of León, and the Hospital of León, Spain.
Gonzalez
Paquita
P
Duran
M Cristina
MC
Molpeceres
Virginia
V
Culebras
Jesús M
JM
Gonzalez-Gallego
Javier
J
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D056741:Cyclin D; D019927:Cyclin E / Q000032:analysis; D051357:Cyclin-Dependent Kinase 2 / Q000032:analysis; D051358:Cyclin-Dependent Kinase 4 / Q000032:analysis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis / Q000502:physiology*; D016213:Cyclins / Q000032:analysis; D003510:Cyclohexanes / Q000494:pharmacology* / Q000627:therapeutic use; D017228:Hepatocyte Growth Factor / Q000032:analysis; D008099:Liver / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D051381:Rats; D017208:Rats, Wistar; D012717:Sesquiterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
D020533:Angiogenesis Inhibitors; C493958:Cdkn1a protein, rat; D056741:Cyclin D; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D003510:Cyclohexanes; D012717:Sesquiterpenes; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D017228:Hepatocyte Growth Factor; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D000077609:O-(Chloroacetylcarbamoyl)fumagillol