Enhancement of the caspase-independent apoptotic sensitivity of pancreatic cancer cells by DHMEQ, an NF-κB inhibitor

Matsumoto, Gaku; Muta, Mariko; Umezawa, Kazuo; Suzuki, Tatsunori; Misumi, Keizo; Takada, Koji; Okamoto, Akira; Toi, Masakazu

doi:10.3892/ijo.27.5.1247

Cited by 12 publications

(20 citation statements)

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“…We have shown that DHMEQ inhibited cell proliferation and survivin expression in KU19-20 cells, suggesting a close relationship between NF-κB and survivin in RCC. A recent study by Matsumoto et al also showed the usefulness of DHMEQ in the treatment of pancreas cancer (20). DHMEQ appears to be a potential candidate for a more effective systemic therapy in the treatment of RCC.…”

Section: Discussionmentioning

confidence: 98%

Survivin associates with cell proliferation in renal cancer cells: Regulation of survivin expression by insulin-like growth factor-1, interferon-γ and a novel NF-κB inhibitor

Sato

Oya²,

Ito

et al. 2006

Int J Oncol

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Abstract. Although survivin has been widely recognized as an attractive target for cancer therapy, the exact mechanism regarding the regulation of survivin and its effect on cell proliferation have yet to be clearly defined in renal cell carcinoma (RCC). We investigated herein the association between survivin expression and cell proliferation in a RCC cell line, KU19-20. In KU19-20 cells, cell proliferation and survivin expression were significantly induced by IGF-1, whereas they were inhibited by a novel NF-κB inhibitor dehydroxymethyl-epoxyquinomicin (DHMEQ) and IFN-Á. The combination of DHMEQ and IFN-Á inhibited cell proliferation synergistically with a pronounced attenuation of survivin expression. Furthermore, treatment with survivinspecific siRNA reduced expression of survivin and significantly inhibited cell proliferation. Survivin expression was thus associated with cell proliferation in KU19-20 cells. The regulation of survivin by IFN-Á and/or an NF-κB inhibitor may therefore be a potential treatment modality for RCC.

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Section: Discussionmentioning

confidence: 98%

Survivin associates with cell proliferation in renal cancer cells: Regulation of survivin expression by insulin-like growth factor-1, interferon-γ and a novel NF-κB inhibitor

Sato

Oya²,

Ito

et al. 2006

Int J Oncol

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“…(14) DHMEQ has been reported to be effective on various hematologic and solid malignancies with constitutively active NF-κB. (15)(16)(17)(18)(19)(20)(21) Therefore, in search for a new modality of PEL therapy based on the idea of molecular targeting, we examined effects of DHMEQ on PEL cells in vitro and in vivo. Our data demonstrated that DHMEQ could abrogate the NF-κB activation transiently and initiate the apoptosis cascade irreversibly without activation of HHV-8 replication.…”

Section: Primary Effusion Lymphoma (Pel) Is a Refractory Malignancy Cmentioning

confidence: 99%

Transient inhibition of NF‐κB by DHMEQ induces cell death of primary effusion lymphoma without HHV‐8 reactivation

et al. 2009

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“…(30) Anticancer activity of DHMEQ was also evaluated in PK-8 pancreatic cancer cells. (31) TNF-α induced NF-κB activation, which was inhibited by DHMEQ. It inhibited expressions of anti-apoptotic c-FLIP and survivin, and induced apoptosis synergistically with TNF-α.…”

Section: Antineoplastic Activity Of Dhmeq In Vivomentioning

confidence: 99%

Inhibition of tumor growth by NF‐κB inhibitors

Umezawa¹

2006

Cancer Science

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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...

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Enhancement of the caspase-independent apoptotic sensitivity of pancreatic cancer cells by DHMEQ, an NF-κB inhibitor

Cited by 12 publications

References 0 publications

Survivin associates with cell proliferation in renal cancer cells: Regulation of survivin expression by insulin-like growth factor-1, interferon-γ and a novel NF-κB inhibitor

Survivin associates with cell proliferation in renal cancer cells: Regulation of survivin expression by insulin-like growth factor-1, interferon-γ and a novel NF-κB inhibitor

Transient inhibition of NF‐κB by DHMEQ induces cell death of primary effusion lymphoma without HHV‐8 reactivation

Inhibition of tumor growth by NF‐κB inhibitors

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