155 E Brush Hill Rd
Elmhurst IL 60126
Medical School: Other - Unknown
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License #: 036094821
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Induction of apoptosis and down regulation of cell cycle proteins in mantle cell lymphoma by flavopiridol treatment. - Leukemia research
Typical mantle cell lymphoma (MCL) is a distinct B-cell non-Hodgkin's lymphoma associated with over-expression of cyclin D1 related to translocation between the IgH and BCL-1 genes. Due to the important functional interaction between cyclin D1 and cyclin dependent kinases, cyclin dependent kinase inhibitors such as flavopiridol are under consideration for treatment of patients with MCL. The present study investigated the in vitro effects of flavopiridol on the MCL cell line (JeKo-1). Flavopiridol at a dose of 10nmol/L induced apoptosis by 6h of treatment as noted by flow cytometric analysis, morphologic examination and Western blotting. The cleavage of procaspase-3 and PARP and the decrease of flavopiridol-induced apoptosis by pan-caspase inhibition suggested that the caspase pathway serves an important role in the apoptotic process. Furthermore, MCL cells exposed to flavopiridol showed down regulation of key cell cycle proteins acting at the restriction point control between the G1 and S phases. The onset of flavopiridol-induced apoptosis also coincided with the down regulation of Mcl-1, anti-apoptotic protein. Collectively, our data indicates that flavopiridol may have significant therapeutic potential in the context of MCL.
Survival role of protein kinase C (PKC) in chronic lymphocytic leukemia and determination of isoform expression pattern and genes altered by PKC inhibition. - American journal of hematology
Recent studies have suggested that protein kinase C (PKC) activation plays an important role in survival of chronic lymphocytic leukemia (CLL). In order to characterize the role of PKC in CLL, we investigated the expression pattern of PKC isoforms in CLL cells (7 cases) and evaluated the effect of PKC inhibition on the survival of CLL cells (20 cases). Expression of the classical PKC isoforms beta and gamma, the novel isoform delta and the atypical isoform zeta was seen in all analyzed patient samples by Western blot analysis. Expression of the PKC isoforms alpha, epsilon, and iota was variable. Following incubation with the PKC inhibitor, safingol, CLL cells underwent marked apoptosis in all cases. In order to characterize the molecular events associated with the apoptotic effect of PKC inhibition, gene expression patterns in CLL cells were evaluated by cDNA-microarray analysis. Following safingol treatment, several genes showed marked downregulation and PKC-related proteins demonstrated decreased hybridization signals. Among these proteins, CREB and Daxx were further studied by using Western blotting, nuclear binding assay and confocal immunofluorescent microscopy. These studies showed significant inhibition of these proteins, consistent with the results of microarray gene analysis. Overall, these findings suggest that PKC activation is important for CLL cell survival and that inhibitors of PKC may have a role in the treatment of patients with CLL.
Protein kinase C-delta is commonly expressed in multiple myeloma cells and its downregulation by rottlerin causes apoptosis. - British journal of haematology
The growth and proliferation of multiple myeloma (MM) cells are influenced by various cytokines produced by bone marrow stromal cells. As cytokine interaction between malignant plasma cells and neighbouring stromal cells is important in the pathogenesis of MM, the understanding of intracellular signalling events elicited by this interaction is of central importance. Recent reports have shown that protein kinase C (PKC) is directly involved in modulating apoptosis in different cells types, including those of haematopoietic neoplasms. In the present study, we analysed the expression patterns of PKC isoforms in the myeloma cell lines U266, RPMI-8226 and K620. This analysis demonstrated common expression of PKC-delta, PKC-iota, PKC- micro and PKC-zeta in all three myeloma cell lines. PKC-delta expression in plasma cells from 11 patients with MM was also shown by immunohistochemistry, utilizing a monoclonal mouse anti-human PKC-delta antibody. U266 cells treated with the broad PKC inhibitor safingol (l-threo-dihydrosphingosine) or the PKC-delta-specific inhibitor rottlerin (3'-[(8-Cinnamoyl-5,7-dihydroxy-2,2-dimethyl-2H-1-benzopyran-6-yl)methyl]-2',4',6'-trihydroxy-5'-methylacetophenone) showed decreased PKC-delta in the particulate fraction and resulted in significant apoptosis. Primary myeloma cells also showed apoptosis after treatment with the PKC inhibitors, as detected by both flow cytometric and morphological evaluation. Our results indicate that PKC-delta is commonly expressed in myeloma cells and plays an important role in plasma cell survival.
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155 E Brush Hill Rd Elmhurst, IL 60126
133 E Brush Hill Rd Suite 202