Inhibitors of the mevalonate pathway as potential therapeutic agents in multiple myeloma.
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 pathway were particularly affected by zoledronate and fluvastatin, and that some of these genetic effects were synergistic. We conclude that the mechanisms of geranylgeranylation inhibition mediated anti-myeloma effects warrant further evaluation and may provide novel targets for future therapeutic development.
Baulch-Brown
Cindy
C
Myeloma Research Group, Department of Clinical Haematology and Bone Marrow Transplantation, Ground Floor, South Block, Alfred Hospital, Commercial Road, Melbourne, Vic. 3004, Australia.
Molloy
Timothy J
TJ
Yeh
Sung Lin
SL
Ma
David
D
Spencer
Andrew
A
D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology* / Q000627:therapeutic use; D004354:Drug Screening Assays, Antitumor; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology* / Q000627:therapeutic use; D000077340:Fluvastatin; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008798:Mevalonic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D000077211:Zoledronic Acid; D003986:Dibenzocycloheptenes
D051017:Apoptosis Regulatory Proteins; D004164:Diphosphonates; D005229:Fatty Acids, Monounsaturated; D000077340:Fluvastatin; D007093:Imidazoles; D007211:Indoles; D008798:Mevalonic Acid; D010880:Piperidines; D011725:Pyridines; D000077211:Zoledronic Acid; C115354:lonafarnib; D003986:Dibenzocycloheptenes