Anti-cancer therapy: Targeting the mevalonate pathway

Kelly M. Swanson, Raymond Hohl

Research output: Contribution to journalReview article

100 Citations (Scopus)

Abstract

The mevalonate pathway has become an important target for anti-cancer therapy. Manipulation of this pathway results in alteration of malignant cell growth and survival in cell culture and animal models, with promising potential for application in human cancers. Mevalonate is synthesized from 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA). Mevalonate is further metabolized to farnesyl pyrophosphate (FPP), which is the precursor for sterols. In addition, the farnesyl moiety from FPP is utilized for post-translational modification of proteins including small GTPases, such as Ras and Ras related proteins, which play a role in malignant transformation of cells. FPP is a precursor for geranylgeranyl pyrophosphate (GGPP), which is similarly involved in post-translational modification of proteins. There has been intense interest in manipulating the pathway through HMG-CoA reductase inhibition. More recently, the focus has been on manipulating the pathway by post-translational modification of key regulatory proteins through farnesyl prenyl transferase (FPTase) or geranylgeranyl prenyl transferase (GGPTase) inhibition. This review focuses on the mevalonate pathway and the application of rational drug therapies to manipulate this pathway. Included in the review are a summary of agents demonstrating success in preclinical investigations such as; farnesyl transferase inhibitors, geranylgeranyl transferase inhibitors, dual inhibitors, statins, bisphosphonates, histone deacetylase inhibitors and other compounds. While these agents have shown preclinical success, translation to success in clinical trials has been more difficult. These clinical trials are reviewed along with evaluation of some of the potential problems with these agents in their clinical application.

Original languageEnglish (US)
Pages (from-to)15-37
Number of pages23
JournalCurrent Cancer Drug Targets
Volume6
Issue number1
DOIs
StatePublished - Feb 1 2006

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Mevalonic Acid
Transferases
Post Translational Protein Processing
Neoplasms
Clinical Trials
Hydroxymethylglutaryl-CoA Reductase Inhibitors
ras Proteins
Histone Deacetylase Inhibitors
Monomeric GTP-Binding Proteins
Diphosphonates
Sterols
Coenzyme A
Therapeutics
Cell Survival
Oxidoreductases
Animal Models
Cell Culture Techniques
Drug Therapy
Growth
farnesyl pyrophosphate

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Cancer Research

Cite this

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title = "Anti-cancer therapy: Targeting the mevalonate pathway",
abstract = "The mevalonate pathway has become an important target for anti-cancer therapy. Manipulation of this pathway results in alteration of malignant cell growth and survival in cell culture and animal models, with promising potential for application in human cancers. Mevalonate is synthesized from 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA). Mevalonate is further metabolized to farnesyl pyrophosphate (FPP), which is the precursor for sterols. In addition, the farnesyl moiety from FPP is utilized for post-translational modification of proteins including small GTPases, such as Ras and Ras related proteins, which play a role in malignant transformation of cells. FPP is a precursor for geranylgeranyl pyrophosphate (GGPP), which is similarly involved in post-translational modification of proteins. There has been intense interest in manipulating the pathway through HMG-CoA reductase inhibition. More recently, the focus has been on manipulating the pathway by post-translational modification of key regulatory proteins through farnesyl prenyl transferase (FPTase) or geranylgeranyl prenyl transferase (GGPTase) inhibition. This review focuses on the mevalonate pathway and the application of rational drug therapies to manipulate this pathway. Included in the review are a summary of agents demonstrating success in preclinical investigations such as; farnesyl transferase inhibitors, geranylgeranyl transferase inhibitors, dual inhibitors, statins, bisphosphonates, histone deacetylase inhibitors and other compounds. While these agents have shown preclinical success, translation to success in clinical trials has been more difficult. These clinical trials are reviewed along with evaluation of some of the potential problems with these agents in their clinical application.",
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Anti-cancer therapy : Targeting the mevalonate pathway. / Swanson, Kelly M.; Hohl, Raymond.

In: Current Cancer Drug Targets, Vol. 6, No. 1, 01.02.2006, p. 15-37.

Research output: Contribution to journalReview article

TY - JOUR

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T2 - Targeting the mevalonate pathway

AU - Swanson, Kelly M.

AU - Hohl, Raymond

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