Synergistic inhibitory effect of apomine and lovastatin on osteosarcoma cell growth

Gatien Moriceau, Anke J. Roelofs, Regis Brion, Francoise Redini, Frank H. Ebetino, Michael J. Rogers, Dominique Heymann

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)750-760
Number of pages11
JournalCancer
Volume118
Issue number3
Early online date12 Jul 2011
DOIs
Publication statusPublished - 1 Feb 2012

Fingerprint

Lovastatin
Osteosarcoma
Growth
Oxidoreductases
Mevalonic Acid
Protein Prenylation
Enzymes
Cell Line
Apoptosis
apomine
ras Proteins
Neoplasms
Diphosphonates
Cell Survival
Esters
Cholesterol
3-hydroxy-3-methylglutaryl-coenzyme A
Bone and Bones

Keywords

  • osteosarcoma
  • apomine
  • lovastatin
  • apoptosis
  • cell cycle

Cite this

Moriceau, G., Roelofs, A. J., Brion, R., Redini, F., Ebetino, F. H., Rogers, M. J., & Heymann, D. (2012). Synergistic inhibitory effect of apomine and lovastatin on osteosarcoma cell growth. Cancer, 118(3), 750-760. https://doi.org/10.1002/cncr.26336

Synergistic inhibitory effect of apomine and lovastatin on osteosarcoma cell growth. / Moriceau, Gatien; Roelofs, Anke J.; Brion, Regis; Redini, Francoise; Ebetino, Frank H.; Rogers, Michael J.; Heymann, Dominique.

In: Cancer, Vol. 118, No. 3, 01.02.2012, p. 750-760.

Research output: Contribution to journalArticle

Moriceau, G, Roelofs, AJ, Brion, R, Redini, F, Ebetino, FH, Rogers, MJ & Heymann, D 2012, 'Synergistic inhibitory effect of apomine and lovastatin on osteosarcoma cell growth', Cancer, vol. 118, no. 3, pp. 750-760. https://doi.org/10.1002/cncr.26336
Moriceau G, Roelofs AJ, Brion R, Redini F, Ebetino FH, Rogers MJ et al. Synergistic inhibitory effect of apomine and lovastatin on osteosarcoma cell growth. Cancer. 2012 Feb 1;118(3):750-760. https://doi.org/10.1002/cncr.26336
Moriceau, Gatien ; Roelofs, Anke J. ; Brion, Regis ; Redini, Francoise ; Ebetino, Frank H. ; Rogers, Michael J. ; Heymann, Dominique. / Synergistic inhibitory effect of apomine and lovastatin on osteosarcoma cell growth. In: Cancer. 2012 ; Vol. 118, No. 3. pp. 750-760.
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AU - Moriceau, Gatien

AU - Roelofs, Anke J.

AU - Brion, Regis

AU - Redini, Francoise

AU - Ebetino, Frank H.

AU - Rogers, Michael J.

AU - Heymann, Dominique

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N2 - 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.

AB - 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.

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JO - Cancer

JF - Cancer

SN - 0008-543X

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ER -