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- W922747079 abstract "3260 Mantle cell lymphoma (MCL) arises from the neoplastic transformation of naive B cells in the mantle zone of the B cell follicle. It is an aggressive and incurable B cell neoplasm. It accounts for 5% to 8% of non-Hodgkin’s lymphomas. Patients with MCL respond initially to chemotherapy but ultimately relapse. Mean survival time is only three to four years. Thus, the need for new treatments that effectively combat MCL is obvious and imperative. Defects in cell cycle regulation and apoptosis are primary events in MCL. It is characterized by the presence of a chromosomal translocation t (11:14)(q13:q32), which results in deregulated cyclin D1 expression. Cyclin D1 overexpression in MCL is thought to play a major role in lymphomagenesis, although the precise mechanisms by which tumor formation and progression occur are not fully understood. Subsets of MCLs also exhibit constitutive activity of two proteins previously implicated in tumor cell survival: the serine/threonine kinase AKT and signal transducer and activator of transcription 3 (Stat3). Toward the search for novel therapies for MCLs, we examined the potential of roscovitine (Rosc), an inhibitor of cyclin dependent kinase (CDK), as a single agent or in combination with either LY294002 (LY), a PI3K/Akt inhibitor, or cucurbitacin-I (CuI), a Jak/Stat3 inhibitor, in inducing apoptosis of various MCL lines as well as in MCL patient samples. Roscovitine or CuI modestly increased the percentage of apoptotic cells (~30%), whereas LY had no effect. However, when added in combination, Rosc/CuI or Rosc/LY induced apoptosis in more than 70% of cells. We also identified three targets of the latter combination: cyclin D1 and the anti-apoptotic proteins myeloid cell leukemia-1 (Mcl-1) and X-linked Inhibitor of Apoptosis (XIAP). Roscovitine eliminated Mcl-1 expression, slightly reduced XIAP abundance and had very little effect on abundance of cyclin D1. Conversely, LY reduced cyclin D1 expression and slightly reduced the abundance of Mcl-1 and XIAP. A larger decrease in XIAP abundance is seen in cultures treated with a combination of Rosc/LY. On the basis of these findings, we suggest that agents that target Mcl-1, XIAP and cyclin D1 will be most effective in inducing apoptosis of human MCLs." @default.
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- W922747079 date "2007-05-01" @default.
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- W922747079 title "Novel combinations with a CDK inhibitor for the treatment of human mantle cell lymphoma cells" @default.
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