Myeloma cell apoptosis and cell cycle inhibition are induced by mycophenolate mofetil

06-16-2006

According to recent research from the United States published in the journal Molecular Cancer Therapeutics, myeloma cell caspase-dependent apoptosis and cell cycle inhibition is induced by the IMP dehydrogenase (IMPDH) inhibitor mycophenolate mofetil (MMF).

"Multiple myeloma is an incurable disease for the majority of patients, therefore requiring new biological targeted therapies. In primary myeloma cells, IMPDH was shown to be consistently overexpressed," wrote N. Takebe and colleagues, University of Maryland. "We therefore tested the IMPDH inhibitor MMF currently available as a clinical therapeutic agent for its antimyeloma activity in vitro."

They continued, "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 mcmol/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," Takebe and coinvestigators wrote.

"MMIF-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. MMIF-treated myeloma cells showed an up-regulation of Bak, which most likely together with Bax resulted in the release of cytochrome c," reported the authors.

They concluded, "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."

Takebe and colleagues published their study in Molecular Cancer Therapeutics (IMP dehydrogenase inhibitor mycophenolate mofetil induces caspase-dependent apoptosis and cell cycle inhibition in multiple myeloma cells. Mol Cancer Ther, 2006;5(2):457-466).

For additional information, contact N. Takebe, University of Maryland, Greenebaum Cancer Center, 655 W Baltimore St., BRB 7-029, Baltimore, MD 21201, USA.

The publisher's contact information for the journal Molecular Cancer Therapeutics is: American Association of Cancer Research, 615 Chestnut St., 17th Floor, Philadelphia, PA 19106-4404, USA.

Keywords: Baltimore, Maryland, United States, Apoptosis, Cancer Therapy, IMP Dehydrogenase, Mycophenolate Mofetil, Multiple Myeloma, Cell Cycle Inhibition, Bone Marrow.

This article was prepared by Clinical Oncology Week editors from staff and other reports. Copyright 2006, Clinical Oncology Week via NewsRx.com.