Targeting NF-kappaB in hematologic malignancies.
The transcription factor nuclear factor kappa B (NF-kappaB) can intervene in oncogenesis by virtue of its capacity to regulate the expression of a plethora of genes that modulate apoptosis, and cell survival as well as proliferation, inflammation, tumor metastasis and angiogenesis. Different reports demonstrate the intrinsic activation of NF-kappaB in lymphoid and myeloid malignancies, including preneoplastic conditions such as myelodysplastic syndromes, underscoring its implication in malignant transformation. Targeting intrinsic NF-kappaB activation, as well as its upstream and downstream regulators, may hence constitute an additional approach to the oncologist's armamentarium. Several small inhibitors of the NF-kappaB-activatory kinase IkappaB kinase, of the proteasome, or of the DNA binding of NF-kappaB subunits are under intensive investigation. Currently used cytotoxic agents can induce NF-kappaB activation as an unwarranted side effect, which confers apoptosis suppression and hence resistance to these drugs. Thus, NF-kappaB inhibitory molecules may be clinically useful, either as single therapeutic agents or in combination with classical chemotherapeutic agents, for the treatment of hematological malignancies.
Centre National de la Recherche Scientifique, UMR8125, Institut Gustave Roussy, 39 rue Camille-Desmoulins, F-94805 Villejuif, France.
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Braun
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Carvalho
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Fabre
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Grosjean
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Fenaux
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Kroemer
D019337:Hematologic Neoplasms / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000628:therapy; D007951:Leukemia, Myeloid / Q000378:metabolism / Q000628:therapy; D008954:Models, Biological; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction
D016328:NF-kappa B