Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most frequent aggressive lymphoma, with a great demand for novel treatments for relapsing and refractory disease. Constitutive activation of the phosphatidyl-inositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is often detected in this lymphoma. Inhibition of this signaling cascade with the pan-class I PI3K inhibitor NVP-BKM120 decreased cell proliferation and increased apoptotic cell death. DLBCL proliferation was further decreased if NVP-BKM120-induced autophagy was blocked. Treatment with NVP-BKM120 was associated with an increase of the pro-apoptotic BH3-only proteins Puma and Bim and down-regulation of the anti-apoptotic Bcl-xL and Mcl-1. Translation of Bcl-xL and Mcl-1 is facilitated by cap-dependent mRNA translation, a process that was partially inhibited by NVP-BKM120. Overall, we demonstrated here the potential of NVP-BKM120 for the treatment of DLBCL.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aminopyridines / pharmacology*
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Apoptosis / drug effects*
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Autophagy / drug effects
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Blotting, Western
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Cell Cycle / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects*
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Cell Survival / drug effects
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Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
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Class I Phosphatidylinositol 3-Kinases / metabolism
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Dose-Response Relationship, Drug
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Flow Cytometry
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Humans
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Lymphoma, Large B-Cell, Diffuse / metabolism
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Lymphoma, Large B-Cell, Diffuse / pathology
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Morpholines / pharmacology*
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Myeloid Cell Leukemia Sequence 1 Protein / genetics
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Myeloid Cell Leukemia Sequence 1 Protein / metabolism
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Protein Biosynthesis / drug effects
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Proto-Oncogene Proteins c-akt / metabolism
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Signal Transduction / drug effects
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TOR Serine-Threonine Kinases / metabolism
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Tumor Cells, Cultured
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bcl-X Protein / genetics
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bcl-X Protein / metabolism
Substances
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Aminopyridines
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MCL1 protein, human
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Morpholines
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Myeloid Cell Leukemia Sequence 1 Protein
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NVP-BKM120
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bcl-X Protein
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Class I Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases