Apomine enhances the antitumor effects of lovastatin on myeloma cells by down-regulating 3-hydroxy-3-methylglutaryl-coenzyme A reductase

Anke J. Roelofs, Claire M. Edwards, R. Graham, G. Russell, F. Hal Ebetino, Michael J. Rogers, Philippa A. Hulley

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Apomine, a 1,1- bisphosphonate- ester with antitumor activity, has previously been reported to strongly down- regulate 3- hydroxy3- methylglutaryl- coenzyme A reductase ( HMG- CoA reductase), the rate- limiting enzyme in the mevalonate pathway responsible for the prenylation of proteins. Here, we show that although apomine down- regulated HMG- CoA reductase protein levels in myeloma cells, it did not inhibit protein prenylation, and apomine- induced apoptosis could not be prevented by mevalonate, indicating that apomine cytotoxicity is independent from its effects on HMG- CoA reductase. Instead, apomine cytotoxicity was prevented by the addition of phosphatidylcholine, which is similar to the previously reported ability of phosphatidylcholine to overcome the cytotoxicity of farnesol, whereas phosphatidylcholine had no effect on down- regulation of HMG- CoA reductase by apomine. These findings raised the possibility that apomine, independent from its own cytotoxic effects, could enhance the antitumor effects of the competitive HMG- CoA reductase inhibitor lovastatin via down- regulating HMG- CoA reductase. Indeed, treatment with apomine in combination with lovastatin resulted in synergistic decreases in viable cell number and induction of apoptosis. At the concentrations used, apomine down- regulated HMG- CoA reductase protein levels without being cytotoxic. Accumulation of unprenylated Rap1A by lovastatin was enhanced in the presence of apomine. Furthermore, synergy was completely prevented by mevalonate, and apomine did not synergize with desoxolovastatin, which does not inhibit HMG- CoA reductase. We conclude that the synergistic drug interaction results from an enhancement by apomine of the effects of lovastatin, mediated by down- regulation of HMG- CoA reductase by apomine. Thus, these findings demonstrate a novel strategy for enhancing the antitumor effects of lovastatin.

Original languageEnglish
Pages (from-to)228-235
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume322
Issue number1
Early online date5 Apr 2007
DOIs
Publication statusPublished - Jul 2007

Keywords

  • HMG-COA-reductase
  • RAB geranylgeranyl transferase
  • coenzyme-A reductase
  • in-vitro
  • mevalonate pathway
  • phosphatidylcholine biosynthesis
  • accelerates degradation
  • protein isoprenylation
  • bone-formation
  • phase-I

Cite this

Apomine enhances the antitumor effects of lovastatin on myeloma cells by down-regulating 3-hydroxy-3-methylglutaryl-coenzyme A reductase. / Roelofs, Anke J.; Edwards, Claire M.; Graham, R.; Russell, G.; Ebetino, F. Hal; Rogers, Michael J.; Hulley, Philippa A.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 322, No. 1, 07.2007, p. 228-235.

Research output: Contribution to journalArticle

Roelofs, Anke J. ; Edwards, Claire M. ; Graham, R. ; Russell, G. ; Ebetino, F. Hal ; Rogers, Michael J. ; Hulley, Philippa A. / Apomine enhances the antitumor effects of lovastatin on myeloma cells by down-regulating 3-hydroxy-3-methylglutaryl-coenzyme A reductase. In: Journal of Pharmacology and Experimental Therapeutics. 2007 ; Vol. 322, No. 1. pp. 228-235.
@article{288abd1b2ecd419b8a8f90e49bfbf783,
title = "Apomine enhances the antitumor effects of lovastatin on myeloma cells by down-regulating 3-hydroxy-3-methylglutaryl-coenzyme A reductase",
abstract = "Apomine, a 1,1- bisphosphonate- ester with antitumor activity, has previously been reported to strongly down- regulate 3- hydroxy3- methylglutaryl- coenzyme A reductase ( HMG- CoA reductase), the rate- limiting enzyme in the mevalonate pathway responsible for the prenylation of proteins. Here, we show that although apomine down- regulated HMG- CoA reductase protein levels in myeloma cells, it did not inhibit protein prenylation, and apomine- induced apoptosis could not be prevented by mevalonate, indicating that apomine cytotoxicity is independent from its effects on HMG- CoA reductase. Instead, apomine cytotoxicity was prevented by the addition of phosphatidylcholine, which is similar to the previously reported ability of phosphatidylcholine to overcome the cytotoxicity of farnesol, whereas phosphatidylcholine had no effect on down- regulation of HMG- CoA reductase by apomine. These findings raised the possibility that apomine, independent from its own cytotoxic effects, could enhance the antitumor effects of the competitive HMG- CoA reductase inhibitor lovastatin via down- regulating HMG- CoA reductase. Indeed, treatment with apomine in combination with lovastatin resulted in synergistic decreases in viable cell number and induction of apoptosis. At the concentrations used, apomine down- regulated HMG- CoA reductase protein levels without being cytotoxic. Accumulation of unprenylated Rap1A by lovastatin was enhanced in the presence of apomine. Furthermore, synergy was completely prevented by mevalonate, and apomine did not synergize with desoxolovastatin, which does not inhibit HMG- CoA reductase. We conclude that the synergistic drug interaction results from an enhancement by apomine of the effects of lovastatin, mediated by down- regulation of HMG- CoA reductase by apomine. Thus, these findings demonstrate a novel strategy for enhancing the antitumor effects of lovastatin.",
keywords = "HMG-COA-reductase, RAB geranylgeranyl transferase, coenzyme-A reductase, in-vitro, mevalonate pathway, phosphatidylcholine biosynthesis, accelerates degradation, protein isoprenylation, bone-formation, phase-I",
author = "Roelofs, {Anke J.} and Edwards, {Claire M.} and R. Graham and G. Russell and Ebetino, {F. Hal} and Rogers, {Michael J.} and Hulley, {Philippa A.}",
year = "2007",
month = "7",
doi = "10.1124/jpet.106.116467",
language = "English",
volume = "322",
pages = "228--235",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "1",

}

TY - JOUR

T1 - Apomine enhances the antitumor effects of lovastatin on myeloma cells by down-regulating 3-hydroxy-3-methylglutaryl-coenzyme A reductase

AU - Roelofs, Anke J.

AU - Edwards, Claire M.

AU - Graham, R.

AU - Russell, G.

AU - Ebetino, F. Hal

AU - Rogers, Michael J.

AU - Hulley, Philippa A.

PY - 2007/7

Y1 - 2007/7

N2 - Apomine, a 1,1- bisphosphonate- ester with antitumor activity, has previously been reported to strongly down- regulate 3- hydroxy3- methylglutaryl- coenzyme A reductase ( HMG- CoA reductase), the rate- limiting enzyme in the mevalonate pathway responsible for the prenylation of proteins. Here, we show that although apomine down- regulated HMG- CoA reductase protein levels in myeloma cells, it did not inhibit protein prenylation, and apomine- induced apoptosis could not be prevented by mevalonate, indicating that apomine cytotoxicity is independent from its effects on HMG- CoA reductase. Instead, apomine cytotoxicity was prevented by the addition of phosphatidylcholine, which is similar to the previously reported ability of phosphatidylcholine to overcome the cytotoxicity of farnesol, whereas phosphatidylcholine had no effect on down- regulation of HMG- CoA reductase by apomine. These findings raised the possibility that apomine, independent from its own cytotoxic effects, could enhance the antitumor effects of the competitive HMG- CoA reductase inhibitor lovastatin via down- regulating HMG- CoA reductase. Indeed, treatment with apomine in combination with lovastatin resulted in synergistic decreases in viable cell number and induction of apoptosis. At the concentrations used, apomine down- regulated HMG- CoA reductase protein levels without being cytotoxic. Accumulation of unprenylated Rap1A by lovastatin was enhanced in the presence of apomine. Furthermore, synergy was completely prevented by mevalonate, and apomine did not synergize with desoxolovastatin, which does not inhibit HMG- CoA reductase. We conclude that the synergistic drug interaction results from an enhancement by apomine of the effects of lovastatin, mediated by down- regulation of HMG- CoA reductase by apomine. Thus, these findings demonstrate a novel strategy for enhancing the antitumor effects of lovastatin.

AB - Apomine, a 1,1- bisphosphonate- ester with antitumor activity, has previously been reported to strongly down- regulate 3- hydroxy3- methylglutaryl- coenzyme A reductase ( HMG- CoA reductase), the rate- limiting enzyme in the mevalonate pathway responsible for the prenylation of proteins. Here, we show that although apomine down- regulated HMG- CoA reductase protein levels in myeloma cells, it did not inhibit protein prenylation, and apomine- induced apoptosis could not be prevented by mevalonate, indicating that apomine cytotoxicity is independent from its effects on HMG- CoA reductase. Instead, apomine cytotoxicity was prevented by the addition of phosphatidylcholine, which is similar to the previously reported ability of phosphatidylcholine to overcome the cytotoxicity of farnesol, whereas phosphatidylcholine had no effect on down- regulation of HMG- CoA reductase by apomine. These findings raised the possibility that apomine, independent from its own cytotoxic effects, could enhance the antitumor effects of the competitive HMG- CoA reductase inhibitor lovastatin via down- regulating HMG- CoA reductase. Indeed, treatment with apomine in combination with lovastatin resulted in synergistic decreases in viable cell number and induction of apoptosis. At the concentrations used, apomine down- regulated HMG- CoA reductase protein levels without being cytotoxic. Accumulation of unprenylated Rap1A by lovastatin was enhanced in the presence of apomine. Furthermore, synergy was completely prevented by mevalonate, and apomine did not synergize with desoxolovastatin, which does not inhibit HMG- CoA reductase. We conclude that the synergistic drug interaction results from an enhancement by apomine of the effects of lovastatin, mediated by down- regulation of HMG- CoA reductase by apomine. Thus, these findings demonstrate a novel strategy for enhancing the antitumor effects of lovastatin.

KW - HMG-COA-reductase

KW - RAB geranylgeranyl transferase

KW - coenzyme-A reductase

KW - in-vitro

KW - mevalonate pathway

KW - phosphatidylcholine biosynthesis

KW - accelerates degradation

KW - protein isoprenylation

KW - bone-formation

KW - phase-I

U2 - 10.1124/jpet.106.116467

DO - 10.1124/jpet.106.116467

M3 - Article

VL - 322

SP - 228

EP - 235

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 1

ER -