Transcription factor NF-κB inhibitors as single therapeutic agents or in combination with classical chemotherapeutic agents for the treatment of hematologic malignancies.
Curr Mol Pharmacol. 2010 Jul 2. Epub 2010 Jul 2. PMID: 20594187
Institute of Hematology and Blood Transfusion, Department of Cell Physiology, U Nemocnice 1, 128 20 Prague 2, Czech Republic. Ota.Fuchs@uhkt.cz.
Nuclear factor-kappaB (NF-kappaB) upregulates the transcription of proteins that promote cell survival, stimulate growth, induce angiogenesis and reduce susceptibility to apoptosis. NF-kappaB 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-kappaB is bound in the cytoplasm to its inhibitor IkappaB, which masks its nuclear localisation signal. Two protein kinases with a high degree of sequence similarity, IKKalpha and IKKbeta, mediate phosphorylation of IkappaB proteins and represent a convergence point for most signal transduction pathways leading to NF-kappaB activation. The overexpression of NF-kappaB and its anti-apoptotic 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-kappaB activation. New agents with NF-kappaB 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-kappaB and downregulates the expression of various NF-kappaB-regulated genes. Triptolide (10-80 ng/ml) induces apoptosis of MM cells and effectively inhibits cell growth of MM cells. NF-kappaB activation can be also inhibited by IKKbeta-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-kappaB.