Inhibition of tumor growth by NF‐κB inhibitors

Abstract

NF-κ κ κκB is a transcription factor that induces inflammatory cytokines and anti-apoptotic proteins. NF-κ κ κ κB is often constitutively activated in human cancers and leukemias, which might increase the malignant character of neoplastic diseases. Therefore, NF-κ κ κ κB inhibitors might be useful as anticancer agents. Our research team designed a new NF-κ κ κ κB inhibitor that is based on the structure of the antibiotic epoxyquomicin C isolated from a microorganism. The designed compound, DHMEQ, inhibited the ligand-induced activation of NF-κ κ κ κB, and it also inhibited the constitutively activated NF-κ κ κ κB in cancer cells. DHMEQ is a unique inhibitor of NF-κ κ κ κB that acts at the level of the nuclear translocation. It inhibited both canonical and non-canonical NF-κ κ κ κB activating pathways. It inhibited various carcinomas and leukemias in animal models without any toxicity, and might be useful as an anticancer agent. Structure and function of NF-κ κ κ κB I n 1986, NF-κB was found to be a nucleoprotein that is bound to the enhancer region of the immunoglobulin κ chain gene.(NF-κB is typically a heterodimer that consists of the p65 (RelA) and p50 proteins.(2) NF-κB might be various heterodimers or homodimers. The NF-κB family of proteins includes p65, p50, p52, c-Rel, RelB, v-Rel, Dorsal, and Dif. Dorsal and Dif are proteins involved in the Drosophila immune system. The Rel subfamily, p50, and p52 proteins contain the Rel homology domain that consists of approximately 300 amino acids. The Rel homology domain is essential for dimerization and binding to DNA, as well as for IκB to bind to NF-κB in order to keep the latter inactive.NF-κB is the transcription factor that binds to the κB sequence. It promotes the transcription of inflammatory cytokines such as IL-1, IL-2, IL-6, IL-8, IL-10 (often suppresses inflammation), IL-12, and TNF-α, cell adhesion moleculers such as E-selectin, ICAM-1, and VCAM-1, and viral proteins. Therefore, NF-κB is primarily an inducer of inflammatory cytokines.(3,4) Its inhibitors could be useful as anti-inflammatory agents. Moreover, NF-κB also induces transcription of anti-apoptotic proteins including IAPs, FLIP, and Bcl-XL. It also induces cyclin D1 that promotes cell growth. Therefore, the NF-κB function inhibitors might also be useful as anticancer agents.Signal transduction pathway of NF-κ κ κ κB activation NF-κB is usually inactive in the cytoplasm without stimulation. As shown in Figure 1, it is activated by extracellular signals such as TNF-α, IL-1, LPS, lipopeptides, and tumor promoters such as phorbol esters.(1,5) The signal transduction pathways from the TNF-α receptor to NF-κB activation have been extensively studied.(6) There are TNFR1 and TNFR2, but TNF-α mainly acts through TNFR1. The cytoplasmic region of TNFR1 contains the death domain that binds to TRADD. For induction of apoptosis, TRADD then activates Fas-associated death domain-containing molecule, which in turn activates caspase 8. For activation of NF-κB, TRADD recruits receptor-interacting protein and TRA...

Gene set enrichment analysis provides insight into novel signalling pathways in breast cancer stem cells

“…TICs are believed to be important at the beginning of tumourigenesis or in its recurrence; therefore, we analysed tumourigenesis at early points from relatively small numbers of TIC-like cells. We transplanted 10 4 cells of CD24 À/low / CD44 þ populations into NOD/SCID mice, as shown in Figure 2, and treated them with DHMEQ, a specific inhibitor for NF-kB (Umezawa, 2006;Supplementary Results;Supplementary Figures 5 and 6). To analyse the effects occurring during the course of tumourigenesis, we began inhibitor treatment 2 days after transplantation.…”

Ligand-dependent EGFR activation induces the co-expression of IL-6 and PAI-1 via the NFkB pathway in advanced-stage epithelial ovarian cancer

“…Gefitinib and erlotinib were from Axon MedChem (Groningen, the Netherlands); the MEK inhibitor UO126 was from Promega (Promega, Madison, WI, USA) and the PI3K inhibitor LY294002 was from Sigma Aldrich. DHMEQ, an NFkB inhibitor that blocks the binding of NFkB to DNA (Umezawa, 2006;Yamamoto et al, 2008), was synthesized by one of the authors (KU). Recombinant human EGF was from Peprotech (Peprotech Inc, Rocky Hill, NJ, USA).…”

Inhibition of NF-κB and Akt pathways by an antibody-avidin fusion protein sensitizes malignant B-cells to cisplatin-induced apoptosis

“…In mammals, the NF-κB contains five members: Rel-A (p65), Rel-B, c-Rel, NF-κB (p50 and its precursor p100) and NF-κB 2 (p52 and its precursor p100), the most abundant being the p65/p50 heterodimer (21). In normal cells, NF-κB activity is tightly controlled by IκB inhibitory proteins.…”