title: Antitumor effects of the combination of cholesterol reducing drugs.
abstract: There are a number of potential mechanisms linking cholesterol homeostasis to processes that are tightly linked with carcinogenesis. Statins, which are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoAR), the rate-limiting enzyme in the mevalonic acid synthesis pathway, exert cytostatic and cytotoxic effects towards tumor cells. It seems that the cytostatic and cytotoxic effects of statins result from blocking protein prenylation, leading to inhibition of isoprenoid compound synthesis. Another compound which affects cholesterol metabolism is the plant alkaloid berberine. The aim of this study was to investigate potential antitumor effects of lovastatin combined with berberine. Combined with berberine, lovastatin appeared to exert potentiated cytostatic and/or cytotoxic effects against human MDA-MB231 breast cancer and murine Panc 02 pancreatic cancer cells. The obtained results indicated that the effect of berberine is not dependent on blocking protein prenylation in cells, and the toxic effect of lovastatin combined with berberine is reversed by addition of the substrates of this pathway to the level brought out by lovastatin alone. Lovastatin-berberine combination caused cell cycle inhibition in G1 phase after 48 h of incubation with drugs. In a Panc 02 pancreatic cancer model in mice, lovastatin-berberine combination slightly, but significantly, slowed down tumor growth. Taking into account the number of patients treated with the investigated drugs one may suppose that the described interactions may be of clinical value.
authors.affiliation: Department of Immunology, Center of Biostructure Research, The Medical University of Warsaw, Banacha 1a, F building, 02-097 Warsaw, Poland. tadeki@interia.pl
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Issat
authors.forename: Dominika
authors.initials: D
authors.lastname: Nowis
authors.forename: Jacek
authors.initials: J
authors.lastname: Bil
authors.forename: Magdalena
authors.initials: M
authors.lastname: Winiarska
authors.forename: Marek
authors.initials: M
authors.lastname: Jakobisiak
authors.forename: Jakub
authors.initials: J
authors.lastname: Golab
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001599:Berberine / Q000494:pharmacology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D004359:Drug Therapy, Combination / Q000379:methods; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000924:Anticholesteremic Agents; D000970:Antineoplastic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D001599:Berberine; D008148:Lovastatin; D008798:Mevalonic Acid