NF-κB as a potential therapeutic target in myelodysplastic syndromes and acute myeloid leukemia.
BACKGROUND
The inactive NF-κB-inhibitor of NF-κB (IκB) complex is activated by stimuli including pro-inflammatory cytokines, mitogens, growth factors and stress-inducing agents. The release of NF-κB facilitates its translocation to the nucleus, where it promotes cell survival by initiating transcription of genes encoding stress-response enzymes, cell-adhesion molecules, pro-inflammatory cytokines and anti-apoptotic proteins. NF-κB and associated regulatory factors (IκB kinase subunits and bcl-3) are implicated in hematological and solid tumour malignancies. NF-κB appears to be involved in cell proliferation control, apoptosis control, angiogenesis promotion and possibly regulation of diffusion of metastases. There are several reports that inhibition of NF-κB as a therapeutic target may have a role in tumour cell death or growth inhibition.


METHODS
We review data about inhibition of NF-κB in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). We describe the molecular mechanisms underlying NF-κB deregulation in these haematological malignancies.


RESULTS
Constitutive activation of NF-κB in the nucleus has been reported in some varieties of MDS/AML. The in vitro and in vivo results of NF-κB inhibition in myeloid malignancies are highlighted.


CONCLUSIONS
NF-κB selective inhibitory drugs may be useful, either as single agents or associated with conventional chemotherapy.
Breccia
Massimo
M
Sapienza University, Department of Human Biotechnologies and Hematology, Rome, Italy. breccia@bce.uniroma1.it
Alimena
Giuliana
G
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D015195:Drug Design; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D056747:Immunomodulation / Q000187:drug effects; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D015398:Signal Transduction / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D020672:I-kappa B Proteins; D016328:NF-kappa B; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex