IMP dehydrogenase inhibitor mycophenolate mofetil induces caspase-dependent apoptosis and cell cycle inhibition in multiple myeloma cells
Multiple myeloma is an incurable disease for the majority of patients, therefore requiring new biological targeted therapies. In primary myeloma cells, IMP dehydrogenase (IMPDH) was shown to be consistently overexpressed. We therefore tested the IMPDH inhibitor mycophenolate mofetil (MMF) currently...
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Published in | Molecular cancer therapeutics Vol. 5; no. 2; pp. 457 - 466 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Association for Cancer Research
01.02.2006
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Subjects | |
Online Access | Get full text |
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Summary: | Multiple myeloma is an incurable disease for the majority of patients, therefore requiring new biological targeted therapies.
In primary myeloma cells, IMP dehydrogenase (IMPDH) was shown to be consistently overexpressed. We therefore tested the IMPDH
inhibitor mycophenolate mofetil (MMF) currently available as a clinical therapeutic agent for its antimyeloma activity in vitro . MMF depleted intracellular guanosine 5′-triphosphate (GTP) levels in myeloma cells. We showed apoptosis induction in myeloma
cell lines and primary myeloma cells between 1 and 5 μmol/L MMF. MMF was also cytotoxic at this concentration in dexamethasone-resistant
and Mcl-1-overexpressed myeloma cell lines shown by the tetrazolium salt XTT assay along with cell survival measured by a
modified flow cytometric assay. Apoptosis was not inhibited by the presence of an antioxidant, suggesting that MMF-induced
apoptosis is less likely to be associated with reactive oxygen species. However, apoptosis was abrogated by exogenously added
guanosine, which activates an alternative pathway for GTP formation, implicating that this effect is directly mediated by
IMPDH inhibition. MMF-induced G 1 -S phase cell cycle arrest and its apoptosis induction mechanism were associated with a caspase-dependent pathway as shown
by alteration of mitochondrial membrane potential and cytochrome c release followed by activation of the caspases. MMF-induced apoptosis was also inhibited by a pan-caspase inhibitor Z-VAD-fmk.
MMF-treated myeloma cells showed an up-regulation of Bak, which most likely together with Bax resulted in the release of cytochrome
c . In summary, MMF attenuates G 1 -S phase cell cycle progression and activates the pathway of mitochondrial dysfunction, leading to cytochrome c release followed by activation of caspases. [Mol Cancer Ther 2006;5(2):457–66] |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1535-7163 1538-8514 |
DOI: | 10.1158/1535-7163.MCT-05-0340 |