(-)-DHMEQ (Dehydroxymethylepoxyquinomicin) is a selective and irreversible NF-κB inhibitor. (-)-DHMEQ directly and covalently binds to specific cysteine residues of Rel family proteins (p65, cRel, RelB, p50). (-)-DHMEQ inhibits NF-κB DNA-binding activity and nuclear translocation. (-)-DHMEQ blocks canonical and non-canonical NF-κB signaling pathways. (-)-DHMEQ reduces the expression of inflammatory cytokines, adhesion molecules, and anti-apoptotic proteins. (-)-DHMEQ can be used in studies related to malignant tumors such as prostate cancer, bladder cancer, adult T-cell leukemia, and pancreatic cancer metastasis, as well as inflammatory diseases including rheumatoid arthritis, sepsis, atopic dermatitis, asthma, and transplant rejection[1-4].
In vitro, pretreatment of INS-1 cells with 1-5µg/mL (-)-DHMEQ for 2 hours followed by co-treatment with 100ng/mL TNF-α for 24 hours inhibited TNF-α-induced NF-κB activation, improved TNF-α-suppressed glucose-stimulated insulin secretion, and ameliorated TNF-α-reduced cell viability[5]. Treatment of MT-2 cells with 1-5µg/mL (-)-DHMEQ for 1-4 hours reduced nuclear p65 protein levels and inhibited NF-κB DNA-binding activity in nuclear extracts[6]. Treatment of A2780 cells with 1.56-100µg/mL (-)-DHMEQ for 24, 48, or 72 hours time-dependently reduced cell viability, decreased colony formation number, and increased the proportion of necrotic and late apoptotic cells[7].
In vivo, C57BL/6 mice treated with 3% dextran sulfate sodium (DSS) received intraperitoneal injections of 20mg/kg (-)-DHMEQ twice daily for 10 consecutive days. (-)-DHMEQ improved disease activity index scores, alleviated colon edema, and reduced histological damage scores[8]. Pristane-treated BALB/c mice received intraperitoneal injections of 12mg/kg (-)-DHMEQ three times per week for 16 consecutive weeks. (-)-DHMEQ reduced serum levels of anti-nucleosome, anti-dsDNA, and anti-histone IgG autoantibodies, and alleviated glomerular damage and renal pathological changes[9]. NOD/SCIDβ2mnull mice bearing TL-Om1 cell subcutaneous xenografts behind the ear received intraperitoneal injections of 12mg/kg (-)-DHMEQ three times per week for 5 consecutive weeks. (-)-DHMEQ inhibited subcutaneous xenograft tumor growth and induced TUNEL-positive apoptotic cells in tumor tissues[10].
References:
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[2] Ma J, Zhang Y, Sugai T, et al. Inhibition of Cellular and Animal Inflammatory Disease Models by NF-κB Inhibitor DHMEQ. Cells. 2021 Sep 1;10(9):2271.
[3] Lin Y, Ukaji T, Koide N, et al. Inhibition of Late and Early Phases of Cancer Metastasis by the NF-κB Inhibitor DHMEQ Derived from Microbial Bioactive Metabolite Epoxyquinomicin: A Review. Int J Mol Sci. 2018 Mar 3;19(3):729.
[4] Umezawa K. Possible role of peritoneal NF-κB in peripheral inflammation and cancer: lessons from the inhibitor DHMEQ. Biomed Pharmacother. 2011 Jul;65(4):252-9.
[5] Saisho Y, Hirose H, Horimai C, et al. Effects of DHMEQ, a Novel Nuclear Factor-κB Inhibitor, on Beta Cell Dysfunction in INS-1 Cells. Endocr J. 2008;55(2):433-438.
[6] Horie K, Ma J, Umezawa K. Inhibition of Canonical NF-κB Nuclear Localization by (-)-DHMEQ via Impairment of DNA Binding. Oncol Res. 2015;22(3):105-115.
[7] Michalak M, Lach MS, Borska S, et al. DHMEQ enhances the cytotoxic effect of cisplatin and carboplatin in ovarian cancer cell lines. Am J Cancer Res. 2021;11(12):6024-6041.
[8] Funakoshi T, Yamashita K, Ichikawa N, et al. A novel NF-κB inhibitor, dehydroxymethylepoxyquinomicin, ameliorates inflammatory colonic injury in mice. J Crohns Colitis. 2012;6(2):215-225.
[9] Qu H, Bian W, Xu Y. A novel NF-kB inhibitor, DHMEQ, ameliorates pristane-induced lupus in mice. Exp Ther Med. 2014 Jul;8(1):100-104.
[10] Ohsugi T, Kumasaka T, Okada S, et al. Dehydroxymethylepoxyquinomicin (DHMEQ) therapy reduces tumor formation in mice inoculated with Tax-deficient adult T-cell leukemia-derived cell lines. Cancer Lett. 2007 Oct 8;257(2):206-215.