Transcription Factor NF-κB Inhibitors as Single Therapeutic Agents or in Combination with Classical Chemotherapeutic Agents for the Treatment of Hematologic Malignancies

Ota      Fuchs

doi:10.2174/1874467211003030098

Abstract

Nuclear factor-kappaB (NF-κB) upregulates the transcription of proteins that promote cell survival, stimulate growth, induce angiogenesis and reduce susceptibility to apoptosis. NF-κB signaling pathway is constitutively activated in myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), lymphomas and in multiple myeloma (MM). Inactive NF-κB is bound in the cytoplasm to its inhibitor IκB, which masks its nuclear localisation signal. Two protein kinases with a high degree of sequence similarity, IKKα and IKKβ, mediate phosphorylation of IκB proteins and represent a convergence point for most signal transduction pathways leading to NF-κB activation. The overexpression of NF-κB and its antiapoptotic cytoprotective effect suggest that it might be a useful therapeutic target for the treatment of hematologic malignancies. Several drugs effective for the treatment of MM, including proteasome inhibitors, thalidomide, lenalidomide and arsenic trioxide, block NF-κB activation. New agents with NF-κB inhibitory activity enhance the anti-MM effects of conventional chemotherapeutic agents and reduce different side-effects. Triptolide (diterpenoid triepoxyde), a purified component of a traditional Chinese medicine, extracted from a shrub-like vine named Trypterygium wilfordii Hook F (TWHF) inhibits transcriptional activation of NF-κB and downregulates the expression of various NF-κB-regulated genes. Triptolide (10-80 ng/ml) induces apoptosis of MM cells and effectively inhibits cell growth of MM cells. NF-κB activation can be also inhibited by IKKβ-selective inhibitors, PS-1145dihydrochloride, MLN120B (both Millennium Pharmaceuticals, Cambridge, MA) and BMS-345541 (Bristol-Myers Squibb, Princeton, NJ). LC-1, the dimethylamino-parthenolide (DMAPT) derivative demonstrated significant cytotoxicity to AML blasts targeting NF-κB.

Keywords: Hematologic malignancies, NF-κB, NF-κB inhibitors, proteasome inhibitors, signal transduction, Nuclear factor-kappaB, angiogenesis, myelodysplastic syndrome, MDS, acute myeloid leukemia, AML, acute lymphocytic leukemia, ALL, chronic myeloid leukemia, CML, chronic lymphocytic leukemia, CLL, lymphomas, multiple myeloma, MM, NF-B, NF-B inhibitors, RelA, Rel, RelB, NF-B1, NF-B2, Rel homology domain, RHD, canonical pathway, noncanonical pathway, casein kinase 2, CD40, –, inducing kinase, NIK, TRAF2, TRAF3, cIAP1, TNF receptor (TNFR), CYLD, Cylin-dromatosis, inhibitor of apoptosis protein, IAP, Telomerase, human telomerase reverse transcriptase, hTERT, vascular endothelial factor, VEGF, matrixmetalloproteinase, dexamethasone, thalidomide, immu-nomodulatory derivatives, IMiDs, arsenic trioxide, As2O3, PR-171, carfilzomib, Histone deacetylase inhibitors, HDACI, Dysoxylum binectariferum, Berbamine