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 α-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.
Footnotes
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This study was supported in part by the Institut National de la Santéet de la Recherche Médicale and by the Association Rhumatisme et Travail, Paris, France.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.136127.
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ABBREVIATIONS: HMG, 3-hydroxy-3-methyl glutaryl; FCS, fetal calf serum; doxorubicin, Adriamycin, (1S,3S)-amino-3 tridesoxy-2,3,6 α-l-lyxohexopyranoside glycoloyl-3 trihydroxy-3,5,12 methoxy-10 dioxo-6,11 naphtacenyl-1; atorvastatin, (3R,5R)-7[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoïc acid; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium; MMP, matrix metalloprotease; DTNB, 5,5′-dithio-bis-(2-nitrobenzoic acid); ARF, alternate reading frame.
- Received January 2, 2008.
- Accepted January 31, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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