Statins potentiate cytostatic/cytotoxic activity of sorafenib but not sunitinib against tumor cell lines in vitro.
The aim of this study was to investigate the potential cytostatic/cytotoxic effects of HMG-CoA reductase inhibitors and two orphan drugs registered for the treatment of advanced renal cell carcinoma, i.e. sorafenib and sunitinib against several different tumor cell lines. Cytostatic/cytotoxic effects were measured using crystal violet or MTT reduction assays. Cell cycle regulation was investigated using flow cytometry and Western blotting. The combination of lovastatin and sorafenib (but not sunitinib) produced synergistic cytostatic/cytotoxic effects against all tested tumor cell lines. In this study, an impairment of the protein prenylation, especially geranylgeranylation, resulted predominantly in the potentiation of the cytostatic/cytotoxic activity of sorafenib, in cell cycle arrest in G1 phase, and, in poor induction of apoptosis. Moreover, due to the fact that it has been well documented that sorafenib compromises the heart function, we studied the interaction of lovastatin and sorafenib using rat cardiomyoblast line H9c2. The combination showed strong synergistic cardiotoxic effects. Statins and tyrosine kinase inhibitors were used at doses that are achievable clinically, which makes the combination promising for future studies, especially in urooncology, bearing in mind possible cardiotoxic effects.
Bil
Jacek
J
Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1a, F Building, 02-097 Warsaw, Poland. jacekbil@mp.pl
Zapala
Lukasz
L
Nowis
Dominika
D
Jakobisiak
Marek
M
Golab
Jakub
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001557:Benzenesulfonates / Q000494:pharmacology* / Q000633:toxicity; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D007211:Indoles / Q000494:pharmacology* / Q000633:toxicity; D008148:Lovastatin / Q000494:pharmacology* / Q000633:toxicity; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D009369:Neoplasms / Q000473:pathology*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D017368:Protein Prenylation; D011725:Pyridines / Q000494:pharmacology* / Q000633:toxicity; D011758:Pyrroles / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D000077157:Sorafenib; D000077210:Sunitinib
D001557:Benzenesulfonates; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011758:Pyrroles; D009536:Niacinamide; D008148:Lovastatin; D000077157:Sorafenib; D000077210:Sunitinib