abt-100 and Disease-Models--Animal

Hutchinson-Gilford progeria syndrome (HGPS) is caused by the accumulation of a farnesylated form of prelamin A (progerin). Previously, we showed that blocking protein farnesylation with a farnesyltransferase inhibitor (FTI) ameliorates the disease phenotypes in mouse model of HGPS (Lmna(HG/+)). However, the interpretation of the FTI treatment studies is open to question in light of recent studies showing that mice expressing a nonfarnesylated version of progerin (Lmna(nHG/+)) develop progeria-like disease phenotypes. The fact that Lmna(nHG/+) mice manifest disease raised the possibility that the beneficial effects of an FTI in Lmna(HG/+) mice were not due to the effects of the drug on the farnesylation of progerin, but may have been due to unanticipated secondary effects of the drug on other farnesylated proteins. To address this issue, we compared the ability of an FTI to improve progeria-like disease phenotypes in both Lmna(HG/+) and Lmna(nHG/+) mice. In Lmna(HG/+) mice, the FTI reduced disease phenotypes in a highly significant manner, but the drug had no effect in Lmna(nHG/+) mice. The failure of the FTI to ameliorate disease in Lmna(nHG/+) mice supports the idea that the beneficial effects of an FTI in Lmna(HG/+) mice are due to the effect of drug on the farnesylation of progerin.

Topics: Adipose Tissue; Animals; Body Weight; Disease Models, Animal; Enzyme Inhibitors; Farnesyltranstransferase; Female; Fibroblasts; Imidazoles; Male; Mice; Phenotype; Prenylation; Progeria; Survival Analysis; Time Factors

Progerias are rare genetic diseases characterized by premature aging. Several progeroid disorders are caused by mutations that lead to the accumulation of a lipid-modified (farnesylated) form of prelamin A, a protein that contributes to the structural scaffolding for the cell nucleus. In progeria, the accumulation of farnesyl-prelamin A disrupts this scaffolding, leading to misshapen nuclei. Previous studies have shown that farnesyltransferase inhibitors (FTIs) reverse this cellular abnormality. We tested the efficacy of an FTI (ABT-100) in Zmpste24-deficient mice, a mouse model of progeria. The FTI-treated mice exhibited improved body weight, grip strength, bone integrity, and percent survival at 20 weeks of age. These results suggest that FTIs may have beneficial effects in humans with progeria.

Topics: Animals; Body Weight; Disease Models, Animal; Enzyme Inhibitors; Farnesyltranstransferase; Female; Hand Strength; Imidazoles; Lamin Type A; Male; Membrane Proteins; Metalloendopeptidases; Mice; Nuclear Proteins; Progeria; Protein Precursors; Protein Prenylation; Rib Fractures; Survival Rate

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.

Topics: Alkyl and Aryl Transferases; Animals; Carcinoma, Hepatocellular; Carrier Proteins; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p27; Diethylnitrosamine; Disease Models, Animal; Enzyme Activation; Enzyme Inhibitors; Farnesyltranstransferase; Female; Humans; Imidazoles; Intracellular Signaling Peptides and Proteins; Liver Neoplasms; Phosphatidylinositol 3-Kinases; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; rap1 GTP-Binding Proteins; ras Proteins; Rats; Rats, Wistar