Chemoprevention of hepatocellular carcinoma : proof of concept in animal models
(2009)
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- Abstract
- (en) In the present work, we have evaluated the possibility of preventing liver carcinogenesis in rats at two stages of development. In the first series of experiments, we induced foci of altered hepatocytes, (FAH) which represent the first events in rodent liver carcinogenesis, using the chemical mutagens diethylnitrosamine (DEN) and acetylaminofluorene (AAF). In the second part of the work, we used repeated weekly injections of DEN only that gave rise to significant fibrosis at 12 weeks and the development of malignant tumours at 16 weeks. We chose to assess the chemopreventive effect of two different drugs: pioglitazone and lanreotide. Pioglitazone is an agonist of PPARγ, itself a member of the nuclear receptor superfamily, responsible for the modulation of a number of metabolic pathways, including cell differentiation, metabolism of lipids and inflammation. The second drug used was lanreotide, a somatostatin analogue that has an inhibitory effect on the release of several hormones, such as growth hormone and serotonine. We showed that both drugs were efficient in the first, pre-neoplastic model, by reducing the size of FAH, decreasing proliferation specifically in FAH by interacting with proteins of the cell cycle. We could also demonstrate that lanreotide increased apoptosis. In the second model, lanreotide was able to diminish the number of established hepatocellular carcinoma (HCC) by decreasing proliferation, in parallel with an anti-fibrotic action. Furthermore, enhanced apoptosis and anti-angiogenic effects were observed when lanreotide was given from the start of the carcinogenic induction by DEN. The cellular mechanisms leading to its effects warrant further investigations. On the contrary, pioglitazone did not prevent the appearance of neoplastic lesions. For these reasons, we did not analyse further its mechanism of action in the second model. Altogether, the results we obtained demonstrate an activity of lanreotide, both at the early onset of liver carcinogenesis, and later on when advanced fibrosis, cirrhosis and HCC are induced.
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Borbath, I. (2009). Chemoprevention of hepatocellular carcinoma : proof of concept in animal models. https://hdl.handle.net/2078.5/131000