Sep 26, 2006

Inhibitors of the mevalonate pathway as potential therapeutic agents in multiple myeloma

Leukemia Research
Cindy Baulch-BrownAndrew Spencer

Abstract

Clinical studies have suggested that bisphosphonates may prolong the survival of sub-sets of myeloma patients. Newer nitrogen containing bisphosphonates such as zoledronate act, at least in part, by inhibiting farnesyl diphosphate synthase and subsequent protein prenylation, furthermore, limited data suggests that zoledronate exerts a direct anti-tumour effect against human myeloma cell lines. We therefore investigated the anti-myeloma potential of zoledronate in comparison to, and in combination with, two other inhibitors of the mevalonate pathway: the HMGCoA reductase inhibitor fluvastatin and the farnesyl transferase inhibitor SCH66336. We found that fluvastatin was able to inhibit the proliferation of myeloma cells more effectively than zoledronate or SCH66336 and that combinations of zoledronate and fluvastatin, but not zoledronate and SCH66336 acted synergistically. Our data indicated that the anti-proliferative effect of mevalonate pathway inhibitors is mediated principally via prevention of geranylgeranylation and is the result of both cell cycle arrest and apoptosis induction. Microarray and quantitative real-time PCR analyses further demonstrated that genes related to apoptosis, cell cycle control, and the mevalonate ...Continue Reading

  • References23
  • Citations17

Mentioned in this Paper

ERCC3 protein, human
Metabolic Process, Cellular
Real-Time Polymerase Chain Reaction
Monoclonal Antibodies
Monoclonal antibodies, antineoplastic
Biochemical Pathway
Microarray Analysis
Pyridines
Exertion
Tissue Membrane

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