Evaluation of Novel Cell Cycle Inhibitors in Mantle Cell Lymphoma.

Signature abnormalities in the cell cycle and apoptotic pathway have been identified in mantle cell lymphoma (MCL), affording the opportunity to develop targeted therapies. Here, we report on a novel class of kinase inhibitors, styryl sulfones, that differ from prior cell cycle inhibitors in that they are not related to purines or pyrimidines. We observed that two closely related compounds, ON013100 and ON01370, altered the growth and cell cycle status of MCL lines and potently inhibited the expression of several important molecules, including CDK4, p53, MDM2, cyclin D, and cyclin B. Using both TUNEL and PARP assays, we found that these compounds caused apoptosis in MCL cells. In addition, using molecular analyses, we observed the modulation of caspase-3 activity but not the expression of Bcl family molecules in these cells. Next, we investigated the cytotoxicity of the MCL lines upon treatment with styryl sulfone compounds in combination with other currently used chemotherapeutic agents, such as doxorubicin (DOX) or vincristine (VCR). We found that the combination of DOX plus styryl sulfone or VCR plus styryl sulfone increased cytotoxicity by one log scale, compared with the single styryl sulfone compound. Thus styryl sulfones alone, or in combination with chemotherapeutic agents, present attractive opportunities for new drug development in MCL.