QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.108.136127v1 325/2/595    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Fromigué, O. Articles by Marie, P. J. PubMed PubMed Citation Articles by Fromigué, O. Articles by Marie, P. J.

CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Statin-Induced Inhibition of 3-Hydroxy-3-Methyl Glutaryl Coenzyme A Reductase Sensitizes Human Osteosarcoma Cells to Anticancer Drugs

Laboratory of Osteoblast Biology and Pathology, Institut National de la Santé et de la Recherche Médicale U606, University Paris 7, Hôpital Lariboisière, Paris, France

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 -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.

Address correspondence to: Dr. Olivia Fromigué, Institut National de la Santé et de la Recherche Médicale U606, Hôpital Lariboisière, 2 rue Ambroise Paré, 75475 Paris cedex 10, France. E-mail: olivia.fromigue{at}larib.inserm.fr