In vivo antitumor activity of the NF-κB inhibitor dehydroxymethylepoxyquinomicin in a mouse model of adult T-cell leukemia

Ohsugi, Takeo; Horie, Ryouichi; Kumasaka, Takashi; Ishida, Akira; Ishida, Takeshi; Yamaguchi, Kazunari; Watanabe, Toshiki; Umezawa, Kazuo; Urano, Toru

doi:10.1093/carcin/bgi095

Cited by 54 publications

(37 citation statements)

References 21 publications

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“…104 DHMEQ induces apoptosis in HTLV-1-transformed cells in a mouse model of ATL. 105 Recently, fucoxanthin, fucoxanthinol and indole-3-carbinol have been reported to inactivate NF-kB and be potentially useful therapeutic agents for patients with ATL. 106,107 However, further clinical studies regarding the activity of NFkB inhibitors on patients with ATL is required for full characterization of their clinical utility.…”

Section: ) Nf-kb Inhibitorsmentioning

confidence: 99%

Treatment of Adult T-cell Leukemia

Uozumi

2010

J Clin Exp Hematopathol

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Adult T-cell Leukemia (ATL) is an aggressive malignant disease of CD4 + T-cells associated with human T-cell leukemia virus type I (HTLV-I). Prognosis of ATL patients is directly correlated to the subtype of ATL. Treatment of the aggressive forms (acute and lymphoma types) of ATL remains inadequate, as most ATL patients receive conventional chemotherapy without stem cell rescue. At present, LSG15 is the standard chemotherapy for the treatment of aggressive ATL, but the efficacy of LSG15 in most patients is transient. To prolong median survival time, additional therapies for maintenance of complete response (CR) are needed after achieving CR by induction chemotherapy. Improved outcome after allogeneic stem cell transplantation (allo-SCT), despite a high incidence of graft-versus-host disease, has been reported. Thus, allogeneic bone marrow transplantation and allogeneic peripheral blood SCT may have great potential for eradication of HTLV-1 and cure of ATL. Recently, reduced-intensity conditioning stem cell transplantation was also reported to be effective for ATL. Although several issues, including selection criteria for patients and sources of stem cells remain to be resolved, allo-SCT may be considered as a treatment option for patients with aggressive ATL. To evaluate whether allo-SCT is more effective than the standard chemotherapy (LSG15) for aggressive ATL, an upfront phase II clinical trial of JCOG-LSG is now being planned. Novel innovative targeted strategies, such as antiretroviral therapy, arsenic trioxide, nuclear factor-kB inhibitors, proteasome inhibitors, histone deacetylase inhibitors, several monoclonal antibodies including anti-CC chemokine receptor 4, anti-folate, purine nucleotide phosphorylase inhibitor, mTOR (mammalian target of rapamycin) inhibitor, bendamustine, small molecule Bcl-2 inhibitors and Tax-targeted immunotherapy, should be promptly studied in order to develop curative treatments for ATL in the near future. 〔J Clin Exp Hematopathol 50(1) : 9-25, 2010〕

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Section: ) Nf-kb Inhibitorsmentioning

confidence: 99%

Treatment of Adult T-cell Leukemia

Uozumi

2010

J Clin Exp Hematopathol

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“…In addition, compounds that inhibit Rel signaling have been used in tumor models. Dehydroxymethylepoxyquinomicin inhibits tumor progression in murine models for T-cell leukemia and multiple myeloma (14,15) and curcumin inhibits metastasis of breast cancer in a nude mouse model (16).…”

Section: Introductionmentioning

confidence: 99%

Dimethylfumarate Impairs Melanoma Growth and Metastasis

et al. 2006

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Dimethylfumarate (DMF) inhibits signals transmitted by Rel proteins and is used for the treatment of inflammatory skin diseases such as psoriasis, but potential effects of DMF on tumor progression have yet not been analyzed. We show that DMF reduced melanoma growth and metastasis in severe combined immunodeficient mouse models. To identify targets of DMF action, we analyzed mRNA expression in DMF-treated melanomas by gene chip arrays. Using BiblioSphere software for data analysis, significantly regulated genes were mapped to Gene Ontology terms cell death, cell growth, and cell cycle. Indeed, we found that DMF inhibited proliferation of human melanoma cells A375 and M24met in vitro. The cell cycle was arrested at the G 2 -M boundary. Moreover, DMF was proapoptotic, as shown by cell cycle analysis and by Annexin V and Apo2.7 staining. These results were confirmed in vivo. DMF reduced proliferation rates of tumor cells as assessed by Ki-67 immunostaining and increased apoptosis as assessed by terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling staining. In conclusion, DMF is antiproliferative and proapoptotic and reduces melanoma growth and metastasis in animal models. (Cancer Res 2006; 66(24): 11888-96)

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“…[23][24][25][26][27] The vital role of NF-B in ATLL is highlighted by the fact that pharmacologic inhibition of this transcription factor induces apoptosis in primary tumor cells. [28][29][30] One difficulty in the study of the biology of primary ATLL is that Tax expression occurs soon after cells are placed in tissue culture or murine models. 23,31 To better understand the mechanisms of malignant growth in ATLL, it is essential to study NF-B and its activation pathways independently of the effects of Tax in primary unmanipulated tumors.…”

Section: Introductionmentioning

confidence: 99%