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Targeting of nuclear factor kappaB Pathways by dehydroxymethylepoxyquinomicin, a novel inhibitor of breast carcinomas: antitumor and antiangiogenic potential in vivo.
Clin Cancer Res. 2005 Feb 01; 11(3):1287-93.CC

Abstract

We previously designed and synthesized the new nuclear factor kappaB (NF-kappaB) inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) derived from the structure of the antibiotic epoxyquinomicin C. We looked into the effect of DHMEQ on cellular phenotypes and tumor growth in mice injected with human breast carcinoma cell line MDA-MB-231 or MCF-7. In estrogen-independent breast adenocarcinoma cell line MDA-MB-231, NF-kappaB is constitutively activated. The addition of DHMEQ (10 microg/mL) completely inhibited the activated NF-kappaB for at least 8 hours. On the other hand, NF-kappaB is not activated in estrogen-dependent MCF-7 cells. In this cell line, DHMEQ completely inhibited the tumor necrosis factor-alpha-induced activation of NF-kappaB. DHMEQ did not inhibit the degradation of IkappaB but inhibited the nuclear translocation of NF-kappaB by both p65/p50 and RelB/p52 pathways. MDA-MB-231 cells secrete interleukin (IL)-6 and IL-8 without stimulation, and DHMEQ decreased the secretion levels of both cytokines. When MDA-MB-231 or MCF-7 cells were stimulated by tumor necrosis factor-alpha, the inhibitory effects of DHMEQ were still maintained. I.p. administration of DHMEQ (thrice a week) significantly inhibited the tumor growth of MDA-MB-231 (12 mg/kg) or MCF-7 (4 mg/kg) in severe combined immunodeficiency mice. No toxicity was observed during the experiment, including the loss of body weight. An immunohistological study on resected MCF-7 tumors showed that DHMEQ inhibited angiogenesis and promoted apoptosis. Furthermore, in Adriamycin-resistant MCF-7 cells highly expressing multidrug resistance gene-1, DHMEQ also exhibited the above capability, including down-regulation of IL-8. Thus, DHMEQ might be a potent drug for the treatment of various breast carcinomas by inhibiting the NF-kappaB activity.

Authors+Show Affiliations

Department of Surgery, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15709200

Citation

Matsumoto, Gaku, et al. "Targeting of Nuclear Factor kappaB Pathways By Dehydroxymethylepoxyquinomicin, a Novel Inhibitor of Breast Carcinomas: Antitumor and Antiangiogenic Potential in Vivo." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 11, no. 3, 2005, pp. 1287-93.
Matsumoto G, Namekawa J, Muta M, et al. Targeting of nuclear factor kappaB Pathways by dehydroxymethylepoxyquinomicin, a novel inhibitor of breast carcinomas: antitumor and antiangiogenic potential in vivo. Clin Cancer Res. 2005;11(3):1287-93.
Matsumoto, G., Namekawa, J., Muta, M., Nakamura, T., Bando, H., Tohyama, K., Toi, M., & Umezawa, K. (2005). Targeting of nuclear factor kappaB Pathways by dehydroxymethylepoxyquinomicin, a novel inhibitor of breast carcinomas: antitumor and antiangiogenic potential in vivo. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 11(3), 1287-93.
Matsumoto G, et al. Targeting of Nuclear Factor kappaB Pathways By Dehydroxymethylepoxyquinomicin, a Novel Inhibitor of Breast Carcinomas: Antitumor and Antiangiogenic Potential in Vivo. Clin Cancer Res. 2005 Feb 1;11(3):1287-93. PubMed PMID: 15709200.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Targeting of nuclear factor kappaB Pathways by dehydroxymethylepoxyquinomicin, a novel inhibitor of breast carcinomas: antitumor and antiangiogenic potential in vivo. AU - Matsumoto,Gaku, AU - Namekawa,Jun-ichi, AU - Muta,Mariko, AU - Nakamura,Tadahiko, AU - Bando,Hiroko, AU - Tohyama,Kazumi, AU - Toi,Masakazu, AU - Umezawa,Kazuo, PY - 2005/2/15/pubmed PY - 2005/6/1/medline PY - 2005/2/15/entrez SP - 1287 EP - 93 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin Cancer Res VL - 11 IS - 3 N2 - We previously designed and synthesized the new nuclear factor kappaB (NF-kappaB) inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) derived from the structure of the antibiotic epoxyquinomicin C. We looked into the effect of DHMEQ on cellular phenotypes and tumor growth in mice injected with human breast carcinoma cell line MDA-MB-231 or MCF-7. In estrogen-independent breast adenocarcinoma cell line MDA-MB-231, NF-kappaB is constitutively activated. The addition of DHMEQ (10 microg/mL) completely inhibited the activated NF-kappaB for at least 8 hours. On the other hand, NF-kappaB is not activated in estrogen-dependent MCF-7 cells. In this cell line, DHMEQ completely inhibited the tumor necrosis factor-alpha-induced activation of NF-kappaB. DHMEQ did not inhibit the degradation of IkappaB but inhibited the nuclear translocation of NF-kappaB by both p65/p50 and RelB/p52 pathways. MDA-MB-231 cells secrete interleukin (IL)-6 and IL-8 without stimulation, and DHMEQ decreased the secretion levels of both cytokines. When MDA-MB-231 or MCF-7 cells were stimulated by tumor necrosis factor-alpha, the inhibitory effects of DHMEQ were still maintained. I.p. administration of DHMEQ (thrice a week) significantly inhibited the tumor growth of MDA-MB-231 (12 mg/kg) or MCF-7 (4 mg/kg) in severe combined immunodeficiency mice. No toxicity was observed during the experiment, including the loss of body weight. An immunohistological study on resected MCF-7 tumors showed that DHMEQ inhibited angiogenesis and promoted apoptosis. Furthermore, in Adriamycin-resistant MCF-7 cells highly expressing multidrug resistance gene-1, DHMEQ also exhibited the above capability, including down-regulation of IL-8. Thus, DHMEQ might be a potent drug for the treatment of various breast carcinomas by inhibiting the NF-kappaB activity. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/15709200/Targeting_of_nuclear_factor_kappaB_Pathways_by_dehydroxymethylepoxyquinomicin_a_novel_inhibitor_of_breast_carcinomas:_antitumor_and_antiangiogenic_potential_in_vivo_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=15709200 DB - PRIME DP - Unbound Medicine ER -