title: 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.
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.
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: P
authors.initials: P
authors.lastname: Yu
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: M N
authors.initials: MN
authors.lastname: Petrus
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: W
authors.initials: W
authors.lastname: Ju
authors.affiliation: 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.
authors.forename: M
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: K C
authors.initials: KC
authors.lastname: Conlon
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Nakagawa
authors.affiliation: Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Maeda
authors.affiliation: Transponics, Jacobus, PA, USA.
authors.forename: R N
authors.initials: RN
authors.lastname: Bamford
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Waldmann
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000097:blood; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D047630:Depsipeptides / Q000494:pharmacology*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000097:blood; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D047368:Tumor Burden / Q000187:drug effects; D001613:beta 2-Microglobulin / Q000097:blood
chemical_list: C529132:2-(((3,5-difluorophenyl)acetyl)amino)-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)propanamide; D000970:Antineoplastic Agents; D001570:Benzodiazepinones; D014408:Biomarkers, Tumor; D001897:Boronic Acids; D047630:Depsipeptides; D053645:Interleukin-2 Receptor alpha Subunit; D016328:NF-kappa B; C497762:Notch1 protein, mouse; D011719:Pyrazines; D051881:Receptor, Notch1; D001613:beta 2-Microglobulin; D000069286:Bortezomib; C087123:romidepsin; D053829:Amyloid Precursor Protein Secretases