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Leukemia. 2015 Mar;29(3):556-66. doi: 10.1038/leu.2014.241. Epub 2014 Aug 14.

Augmented efficacy with the combination of blockade of the Notch-1 pathway, bortezomib and romidepsin in a murine MT-1 adult T-cell leukemia model.

Author information

1
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
2
1] Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA [2] Laboratory Animal Science Program, SAIC-Frederick Inc., NCI-Frederick, Frederick, MD, USA.
3
Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan.
4
Transponics, Jacobus, PA, USA.

Abstract

Adult T-cell leukemia (ATL) is an aggressive malignancy caused by human T-cell lymphotropic virus-1. There is no accepted curative therapy for ATL. We have reported that certain ATL patients have increased Notch-1 signaling along with constitutive activation of the nuclear factor-κB pathway. Physical and functional interaction between these two pathways provides the rationale to combine the γ-secretase inhibitor compound E with the proteasome inhibitor bortezomib. Moreover, romidepsin, a histone deacetylase inhibitor, has demonstrated major antitumor action in leukemia/lymphoma. In this study, we investigated the therapeutic efficacy of the single agents and the combination of these agents in a murine model of human ATL, the MT-1 model. Single and double agents inhibited tumor growth as monitored by tumor size (P<0.05), and prolonged survival of leukemia-bearing mice (P<0.05) compared with the control group. The combination of three agents significantly enhanced the antitumor efficacy as assessed by tumor size, tumor markers in the serum (human soluble interleukin-2 receptor-α and β2-microglobulin) and survival of the MT-1 tumor-bearing mice, compared with all other treatment groups (P<0.05). Improved therapeutic efficacy obtained by combining compound E, bortezomib and romidepsin supports a clinical trial of this combination in the treatment of ATL.

PMID:
25118879
PMCID:
PMC4329116
DOI:
10.1038/leu.2014.241
[Indexed for MEDLINE]
Free PMC Article

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