Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0079731 (B-cell lymphoma)
 16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Flavopiridol is active against chronic lymphocytic leukemia (CLL) cells in vitro and in the treatment of advanced stage disease, but the mechanisms of these actions remain unclear. Originally developed as a general cyclin-dependent kinase inhibitor, flavopiridol is a potent transcriptional suppressor through the inhibition of positive transcription elongation factor b (P-TEFb; CDK9/cyclin T). P-TEFb phosphorylates the C-terminal domain (CTD) of RNA polymerase II to promote transcriptional elongation. Because most CLL cells are not actively cycling, and their viability is dependent upon the continuous expression of antiapoptotic proteins, we hypothesized that flavopiridol induces apoptosis in CLL cells through the transcriptional down-regulation of such proteins. This study demonstrated that flavopiridol inhibited the phosphorylation of the CTD of RNA polymerase II in primary CLL cells and reduced RNA synthesis. This was associated with a decline of the transcripts and the levels of short-lived antiapoptotic proteins such as myeloid cell leukemia 1 (Mcl-1), and resulted in the induction of apoptosis. The B-cell lymphoma 2 (Bcl-2) protein level remained stable, although its mRNA was consistently reduced, suggesting that the outcome of transcriptional inhibition by flavopiridol is governed by the intrinsic stability of the individual transcripts and proteins. The dependence of CLL-cell survival on short-lived oncoproteins may provide the biochemical basis for the therapeutic index in response to flavopiridol.
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PMID:Transcription inhibition by flavopiridol: mechanism of chronic lymphocytic leukemia cell death. 1597 45

Flavopiridol is a cyclin-dependent kinase (CDK) inhibitor that promotes cell cycle arrest. We aimed to examine the anti-proliferative effects of the flavopiridol and oxaliplatin combination on p16INK4A deficient melanoma cells B16F10 and also its apoptotic effects on a subcutaneously injected B16F10 allograft melanoma tumor model. Flavopiridol and oxaliplatin treated B16F10 cell viability was determined by MTT assay. C57BL6 mice were injected with B16F10 cells and treated with flavopiridol after tumor implantation. BRAF and BCL2L1 mRNA expression levels were measured using reverse transcription-polymerase chain reaction (RT-PCR). Caspase 9 and caspase 3/7 activity were determined by activity assay kits. Proliferating cell nuclear antigen (PCNA) and B-cell lymphoma 2 (BCL-2) protein expression levels were analyzed immunohistochemically. Flavopiridol and oxaliplatin decreased cell death. Flavopiridol enhanced caspase 3/7 and caspase 9 activities in vitro and in vivo in a dose dependent manner via the mitochondrial apoptotic pathway. Even though there was a significant increase in Bcl-2 staining, PCNA staining was decreased in flavopiridol-administered mice. Decreased PCNA expression showed antiproliferative effects of flavopiridol which might be the result of cell-cycle arrest. Flavopiridol can be used as a cell cycle inhibitor.
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PMID:Flavopiridol Induces Apoptosis via Mitochondrial Pathway in B16F10 Murine Melanoma Cells and a Subcutaneous Melanoma Tumor Model. 2714 23