pitavastatin and geranylgeraniol

Pre-clinical and retrospective studies of patients using statins to reduce plasma cholesterol have suggested that statins may be useful to treat cancer. However, prospective clinical trials have yet to demonstrate significant efficacy. We have previously shown that this is in part because a hydrophobic statin with a long half-life is necessary. Pitavastatin, the only statin with this profile, has not undergone clinical evaluation in oncology. The target of pitavastatin, hydroxymethylglutarate coenzyme-A reductase (HMGCR), was found to be over-expressed in all ovarian cancer cell lines examined and upregulated by mutated TP53, a gene commonly altered in ovarian cancer. Pitavastatin-induced apoptosis was blocked by geranylgeraniol and mevalonate, products of the HMGCR pathway, confirming that pitavastatin causes cell death through inhibition of HMGCR. Solvent extracts of human and mouse food were also able to block pitavastatin-induced apoptosis, suggesting diet might influence the outcome of clinical trials. When nude mice were maintained on a diet lacking geranylgeraniol, oral pitavastatin caused regression of Ovcar-4 tumour xenografts. However, when the animal diet was supplemented with geranylgeraniol, pitavastatin failed to prevent tumour growth. This suggests that a diet containing geranylgeraniol can limit the anti-tumour activity of pitavastatin and diet should be controlled in clinical trials of statins.

Topics: Animals; Cell Line; Cell Line, Tumor; Cells, Cultured; Diet; Diterpenes; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mice, Nude; Mice, SCID; Ovarian Neoplasms; Quinolines; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Diterpenes; Female; Geranyltranstransferase; GTP Phosphohydrolases; Humans; Imidazoles; Leucine; Mevalonic Acid; Naphthalenes; Ovarian Neoplasms; Quinolines; Zoledronic Acid

ATP binding cassette A1 (ABCA1) is responsible in vivo for the formation of HDL by promoting the lipidation of apoprotein A-I (apoA-I) via cholesterol and phospholipid efflux from the liver. Treatment of patients with statins produces an increase in HDL plasma level, but the underlying mechanism is not completely understood. In this work we investigated the ability of pitavastatin to modulate ABCA1-mediated efflux from Fu5AH rat hepatoma cells, that here we demonstrate to express functional ABCA1 upon treatment with 22OH/cRA. In both basal and ABCA1 expressing cells pitavastatin 0.1-50microM induced a dose-dependent increase in cholesterol efflux to apoA-I; this effect was reversed by mevalonate or geranyl geraniol. A stimulatory effect was also observed on phospholipid efflux. Similar results were obtained with compactin, suggesting a class-related effect of statins. These results indicate a potential mechanism for the improvement in HDL plasma profile observed in patients treated with statins.

Topics: Animals; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters; Biological Transport; Carcinoma, Hepatocellular; Cell Line, Tumor; Cholesterol; Diterpenes; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Lipid Metabolism; Liver Neoplasms; Mevalonic Acid; Quinolines; Rats