TY - JOUR
T1 - Inhibitors of the mevalonate pathway as potential therapeutic agents in multiple myeloma
AU - Baulch-Brown, Cindy
AU - Molloy, Timothy J
AU - Yeh, Sung Lin
AU - Ma, David
AU - Spencer, Andrew
PY - 2007
Y1 - 2007
N2 - 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. (c) 2006 Elsevier Ltd. All rights reserved.
AB - 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. (c) 2006 Elsevier Ltd. All rights reserved.
UR - http://www.elsevier.com/locate/leukres
M3 - Article
SN - 0145-2126
VL - 31
SP - 341
EP - 352
JO - Leukemia Research
JF - Leukemia Research
IS - 3
ER -