title: Synergistic inhibitory effect of apomine and lovastatin on osteosarcoma cell growth.
abstract: BACKGROUND
  Osteosarcoma is the most frequent malignant primary bone tumor that occurs mainly in the young, with an incidence peak observed at age 18 years. Both apomine and lovastatin have antitumor activity in a variety of cancer cell lines. Apomine, a 1,1-bisphosphonate-ester, increases the rate of degradation of 3-hydroxy-3 methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the mevalonate pathway, whereas lovastatin competitively inhibits HMG-CoA reductase enzyme activity, thereby preventing protein prenylation and cholesterol synthesis.
  
  
  METHODS
  The authors of this report investigated the effect of combined treatment with apomine and lovastatin in vitro on human and murine osteosarcoma cell lines and in vivo using a murine syngeneic model of osteosarcoma. Apomine and lovastatin synergistically decreased viability and induced apoptosis in both murine and human osteosarcoma cell lines.
  
  
  RESULTS
  Combined apomine and lovastatin strongly decreased HMG-CoA reductase enzyme levels compared with lovastatin treatment alone. Consequently, the accumulation of unprenylated ras-related protein 1A induced by lovastatin was enhanced in the presence of apomine. All synergistic effects on cell viability, apoptosis, and protein prenylation were overcome by the addition of mevalonate or geranylgeraniol, 2 mevalonate pathway intermediates downstream from the target enzyme, HMG-CoA reductase. This confirmed that the mechanism of synergy in osteosarcoma cells is through augmented inhibition of HMG-CoA reductase. Finally, treatment of POS-1 osteosarcoma-bearing mice with a combination of apomine and lovastatin significantly reduced tumor progression in these mice compared with single treatments, which had no effect at the doses used.
  
  
  CONCLUSIONS
  The results from this study revealed that combination therapy with apomine and lovastatin may be a novel treatment strategy for osteosarcoma.
authors.affiliation: National Institute of Health and Medical Research, Nantes, France.
authors.forename: Gatien
authors.initials: G
authors.lastname: Moriceau
authors.forename: Anke J
authors.initials: AJ
authors.lastname: Roelofs
authors.forename: Régis
authors.initials: R
authors.lastname: Brion
authors.forename: Françoise
authors.initials: F
authors.lastname: Redini
authors.forename: Frank H
authors.initials: FH
authors.lastname: Ebetion
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rogers
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004164:Diphosphonates / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology; D017368:Protein Prenylation / Q000187:drug effects; D051381:Rats; D014407:Tumor Cells, Cultured
chemical_list: D004164:Diphosphonates; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C407151:apomine; D008148:Lovastatin