Abstract
Treatment of hepatocellular carcinoma raised on cirrhotic liver represents a major endeavor because surgery and chemotherapeutic management fail to improve the clinical course of the disease. Chemoprevention could represent an important means to inhibit the process of hepatocarcinogenesis. Farnesyltransferase inhibitors are a class of drugs blocking the growth of tumor cells with minimal toxicity towards normal cells. In the present study, we investigated the effects of a novel farnesyltransferase inhibitor, ABT-100, on human liver cancer cell lines, HepG2 and Huh7, and on an animal model of hepatocarcinogenesis. ABT-100 inhibited HepG2 and Huh7 cell growth as well as the invading ability of Huh7 on Matrigel. In HepG2 and Huh7 cells, ABT-100 inhibited growth factor-stimulated phosphoinositide 3-kinase and Akt/protein kinase B activity. Furthermore, ABT-100 inhibited Akt-dependent p27(Kip1) phosphorylation and this event was associated with increased levels of p27(Kip1) in the nucleus and reduced activity of the cyclin-dependent kinase 2. Moreover, ABT-100 treatment resulted in a significant reduction in tumor incidence and multiplicity. Taken together, these findings identify a mechanism of ABT-100 function and show the efficacy of ABT-100 as a chemopreventive agent of hepatocellular carcinoma.
Highlights
Treatment of hepatocellular carcinoma raised on cirrhotic liver represents a major endeavor because surgery and chemotherapeutic management fail to improve the clinical course of the disease
ABT-100 treatment resulted in a significant reduction in tumor incidence and multiplicity. Taken together, these findings identify a mechanism of ABT-100 function and show the efficacy of ABT-100 as a chemopreventive agent of hepatocellular carcinoma
Survival remains poor for most patients with hepatocellular carcinoma, which is due to the aggressiveness of the lesions at the time of diagnosis and the lack of an effective therapy (1)
Summary
Treatment of hepatocellular carcinoma raised on cirrhotic liver represents a major endeavor because surgery and chemotherapeutic management fail to improve the clinical course of the disease. Most of the time continuous and irregular proliferation associated with inflammation may produce genetic cellular abnormalities with development of hepatocellular carcinoma (2 – 4). This mechanism is responsible for the common association between cancer and cirrhosis. Studies aimed at hepatocellular carcinoma prevention should consider cirrhosis as a precancerous condition Another important point to underline is that surgery and chemotherapeutic management of hepatocellular carcinoma fail to improve the clinical course of the disease. Farnesyltransferase inhibitors are a new class of drugs which block the growth of tumors with minimal toxicity in normal cells (6). Previous studies have shown that inhibition of Ras farnesylation blocks Ras-mediated cellular transformation (7 – 10)
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