title: Statin-induced inhibition of 3-hydroxy-3-methyl glutaryl coenzyme a reductase sensitizes human osteosarcoma cells to anticancer drugs.
abstract: Osteosarcoma is the most common primary bone tumor in children and young adults. Resistance to chemotherapeutic drugs is a major problem that is responsible for the failure of treatment. This points to the need for increasing the responsiveness to cytotoxic drugs. We previously showed that lipophilic statins induce apoptosis in human osteosarcoma cells. In this study, we investigated the effects of atorvastatin [(3R,5R)-7[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoïc acid] in combination with chemotherapeutic drugs on human osteosarcoma cell apoptosis, invasion, and migration. We report here that atorvastatin enhances the reduced cell viability induced by the anticancer drugs doxorubicin (Adriamycin; (1S,3S)-amino-3 tridesoxy-2,3,6 alpha-l-lyxo-hexopyranoside glycoloyl-3 trihydroxy-3,5,12 methoxy-10 dioxo-6,11 naphtacenyl-1) and cisplatin in human osteosarcoma cells. In particular, we found that atorvastatin enhances the induction of osteosarcoma cell apoptosis by anticancer drugs. In addition, we show that atorvastatin enhances the inhibitory effect of anticancer drugs on osteosarcoma cell migration. Moreover, atorvastatin and chemotherapeutic drugs had additive inhibitory effects on osteosarcoma cell invasion. In consistent tests, atorvastatin further augmented the reduction of matrix metalloprotease 2 activity induced by doxorubicin or cisplatin in osteosarcoma cells. The results show for the first time that atorvastatin sensitizes osteosarcoma cells to anticancer drugs, resulting in reduced cell viability, migration, and invasion, which suggest a strategy to improve the response to chemotherapy and reduce tumorigenesis in human osteosarcoma.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U606, Hôpital Lariboisière, 2 rue Ambroise Paré, 75475 Paris cedex 10, France. olivia.fromigue@larib.inserm.fr
authors.forename: Olivia
authors.initials: O
authors.lastname: Fromigué
authors.forename: Zahia
authors.initials: Z
authors.lastname: Hamidouche
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Marie
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000069059:Atorvastatin; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011758:Pyrroles / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D004317:Doxorubicin; D000069059:Atorvastatin; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D002945:Cisplatin