Anti-tumor activity of dehydroxymethylepoxyquinomicin against human oral squamous cell carcinoma cell lines in vitro and in vivo

Yasuda, Arisa; Kondo, Seiji; Nagumo, Tatsuhito; Tsukamoto, Hikari; Mukudai, Yoshiki; Umezawa, Kazuo; Shintani, Satoru

doi:10.1016/j.oraloncology.2011.03.001

Cited by 20 publications

(21 citation statements)

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“…Mice treated with DHMEQ (10 mg/kg body weight) once a day for 17 days had significantly smaller tumor weights as compared to the controls, without side effects. Similar observations were reported in the animal models for bladder cancer [37], oral squamous cell carcinoma [38], thyroid cancer [35] and hepatoma [39].…”

Section: Discussionsupporting

confidence: 86%

“…DHMEQ inhibits NF-κB transcriptional activity via blocking its translocation into the nucleus [40], [41]. The agent suppresses growth of various tumors, such as hormone-refractory prostate cancer, multiple myeloma, thyroid cancer cell, breast cancer, glioblastoma and squamous cell carcinoma in vitro and also in tumor-xenografted mice without any apparent side effects [38], [42]. Several chemicals and plant extracts were shown to suppress growth and induce apoptosis of CCA via inactivation of NF-κB, e.g., caffeic acid phenethyl ester [43], and curcumin [44].…”

Section: Discussionmentioning

confidence: 99%

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Aberrant Expression of NF-κB in Liver Fluke Associated Cholangiocarcinoma: Implications for Targeted Therapy

et al. 2014

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BackgroundUp-regulation and association of nuclear factor kappa B (NF-κB) with carcinogenesis and tumor progression has been reported in several malignancies. In the current study, expression of NF-κB in cholangiocarcinoma (CCA) patient tissues and its clinical significance were determined. The possibility of using NF-κB as the therapeutic target of CCA was demonstrated.MethodologyExpression of NF-κB in CCA patient tissues was determined using immunohistochemistry. Dehydroxymethylepoxyquinomicin (DHMEQ), a specific NF-κB inhibitor, was used to inhibit NF-κB action. Cell growth was determined using an MTT assay, and cell apoptosis was shown by DNA fragmentation, flow cytometry and immunocytofluorescent staining. Effects of DHMEQ on growth and apoptosis were demonstrated in CCA cell lines and CCA-inoculated mice. DHMEQ-induced apoptosis in patient tissues using a histoculture drug response assay was quantified by TUNEL assay.Principal FindingsNormal bile duct epithelia rarely expressed NF-κB (subunits p50, p52 and p65), whereas all CCA patient tissues (n = 48) over-expressed all NF-κB subunits. Inhibiting NF-κB action by DHMEQ significantly inhibited growth of human CCA cell lines in a dose- and time-dependent manner. DHMEQ increased cell apoptosis by decreasing the anti-apoptotic protein expressions–Bcl-2, XIAP–and activating caspase pathway. DHMEQ effectively reduced tumor size in CCA-inoculated mice and induced cell apoptosis in primary histocultures of CCA patient tissues.ConclusionsNF-κB was over-expressed in CCA tissues. Inhibition of NF-κB action significantly reduced cell growth and enhanced cell apoptosis. This study highlights NF-κB as a molecular target for CCA therapy.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Aberrant Expression of NF-κB in Liver Fluke Associated Cholangiocarcinoma: Implications for Targeted Therapy

et al. 2014

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“…NF-κB inhibitor DHMEQ (dehydroxymethylepoxyquinomicin) is designed to bind members of the Rel family and inhibit their DNA-binding activity. 41,[49][50][51][52] In conclusion, we identified marked upregulation of IL10 and IL10R in both GCB and ABC subtypes of DLBCLs and determined that blocking the cell surface receptor results in induction of cell death by cell cycle arrest and apoptosis. This is a novel approach that has not been used before.…”

Section: Discussionmentioning

confidence: 76%

IL10 receptor is a novel therapeutic target in DLBCLs

et al. 2015

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Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease with marked genomic instability and variable response to conventional R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy. More clinically aggressive cases of DLBCLs have high level of circulating interleukin 10 (IL10) cytokine and evidence of activated intracellular STAT3 (signal transducer and activator of transcription 3) signaling. We investigated the role of IL10 and its surface receptor in supporting the neoplastic phenotype of DLBCLs. We determined that IL10RA gene is amplified in 21% and IL10RB gene in 10% of primary DLBCLs. Gene expression of IL10, IL10RA and IL10RB was markedly elevated in DLBCLs. We hypothesized that DLBCLs depend for their proliferation and survival on IL10-STAT3 signaling and that blocking the IL10 receptor (IL10R) would induce cell death. We used anti-IL10R blocking antibody, which resulted in a dose-dependent cell death in all tested activated B-cell-like subtype of DLBCL cell lines and primary DLBCLs. Response of germinal center B-cell-like subtype of DLBCL cell lines to anti-IL10R antibody varied from sensitive to resistant. Cells underwent cell cycle arrest, followed by induction of apoptosis. Cell death depended on inhibition of STAT3 and, to a lesser extent, STAT1 signaling. Anti-IL10R treatment resulted in interruption of IL10-IL10R autostimulatory loop. We thus propose that IL10R is a novel therapeutic target in DLBCLs.

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“…The antitumor effects of DHMEQ have been continually reported in vitro and in in vivo models [30–37]. Compared to other NF- κ B inhibitors, this drug is distinctive by covalently binding to the highly conserved Cys38 of the Rel family members (p65, cRel, RelB, and p50), a residue that is essential for NF- κ B DNA-binding and transcriptional activity [8].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of NF-κB by Dehydroxymethylepoxyquinomicin Suppresses Invasion and Synergistically Potentiates Temozolomide and γ-Radiation Cytotoxicity in Glioblastoma Cells

Brassesco

Roberto

Morales

et al. 2013

Chemotherapy Research and Practice

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Despite advances in neurosurgery and aggressive treatment with temozolomide (TMZ) and radiation, the overall survival of patients with glioblastoma (GBM) remains poor. Vast evidence has indicated that the nuclear factor NF-κB is constitutively activated in cancer cells, playing key roles in growth and survival. Recently, Dehydroxymethylepoxyquinomicin (DHMEQ) has shown to be a selective NF-κB inhibitor with antiproliferative properties in GBM. In the present study, the ability of DHMEQ to surmount tumor's invasive nature and therapy resistance were further explored. Corroborating results showed that DHMEQ impaired cell growth in dose- and time-dependent manners with G2/M arrest when compared with control. Clonogenicity was also significantly diminished with increased apoptosis, though necrotic cell death was also observed at comparable levels. Notably, migration and invasion were inhibited accordingly with lowered expression of invasion-related genes. Moreover, concurrent combination with TMZ synergistically inhibited cell growth in all cell lines, as determined by proliferation and caspase-3 activation assays, though in those that express O6-methylguanine-DNA methyltransferase, the synergistic effects were schedule dependent. Pretreatment with DHMEQ equally sensitized cells to ionizing radiation. Taken together, our results strengthen the potential usefulness of DHMEQ in future therapeutic strategies for tumors that do not respond to conventional approaches.

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Anti-tumor activity of dehydroxymethylepoxyquinomicin against human oral squamous cell carcinoma cell lines in vitro and in vivo

Cited by 20 publications

References 19 publications

Aberrant Expression of NF-κB in Liver Fluke Associated Cholangiocarcinoma: Implications for Targeted Therapy

Aberrant Expression of NF-κB in Liver Fluke Associated Cholangiocarcinoma: Implications for Targeted Therapy

IL10 receptor is a novel therapeutic target in DLBCLs

Inhibition of NF-κB by Dehydroxymethylepoxyquinomicin Suppresses Invasion and Synergistically Potentiates Temozolomide and γ-Radiation Cytotoxicity in Glioblastoma Cells

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