Inhibition of tumor growth by NF-kappaB inhibitors

Abstract

NF-kappaB is a transcription factor that induces inflammatory cytokines and anti-apoptotic proteins. NF-kappaB is often constitutively activated in human cancers and leukemias, which might increase the malignant character of neoplastic diseases. Therefore, NF-kappaB inhibitors might be useful as anticancer agents. Our research team designed a new NF-kappaB 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-kappaB, and it also inhibited the constitutively activated NF-kappaB in cancer cells. DHMEQ is a unique inhibitor of NF-kappaB that acts at the level of the nuclear translocation. It inhibited both canonical and non-canonical NF-kappaB activating pathways. It inhibited various carcinomas and leukemias in animal models without any toxicity, and might be useful as an anticancer agent.

Figure 1

Signal transduction for activation of transcription factor NF‐κB.

Figure 2

Panepoxydone and cycloepoxydone, naturally occurring inhibitors of transcription factor NF‐κB.

Figure 3

Molecular design of DHMEQ based on epoxyquinomicin C.

Figure 4

Inhibition of LPS‐induced p65 nuclear translocation by DHMEQ in RAW264.7 cells. Cells were treated with LPS and 10 µg/mL DHMEQ for 10 min. Nuclear translocation of p65 was detected by FITC‐labeled antip65NLS antibody and analyzed by confocal microscopy. +, reagent added; –, reagent not added. (Reproduced from Suzuki and Umezawa, with permission from Biomedicine and Pharmacotherapy.)

Figure 5

Canonical and non‐canonical NF‐κB activating pathways. Both pathways can be inhibited by DHMEQ. Selective inhibition of NF‐κB by DHMEQ. Canonical pathway has a role mainly on innate immunity, inflammation, and cell survival, while non‐canonical pathway on B‐cell maturation and humoral immunity. BcAF, B‐cell activating factor; CD40L, CD40 ligand.

Figure 6

Inhibition of constitutively activated NF‐κB by DHMEQ in estrogen‐independent breast adenocarcinoma cell line MDA‐MB‐231. Ab, antibodies. (Reproduced from Matsumoto G, et al. (2005), with permission from Clinical Cancer Research.)

Figure 7

Anticancer activity of DHMEQ on prostate carcinoma. Human prostate carcinoma JCA‐1 cells were implanted s.c. When animals had developed palpable tumors, they were given 8 mg/kg DHMEQ, i.p., once daily for 14 days. The y‐axis shows the volume of the tumor in cm³. *P < 0.01. (Reproduced from Kikuchi E, et al., with permission from Cancer Research.)

Figure 8

Anticancer and anti‐inflammatory activities of DHMEQ in vivo.

Figure 9

Possible enhancement of tumor growth by inflammation. DHMEQ might inhibit inflammation caused by both cancer cells and tumor‐associated macrophages. PGs, prostaglandins; VEGF, vascular endothelial growth factor.