title: Preclinical efficacy of the synthetic retinoid ST1926 for treating adult T-cell leukemia/lymphoma.
abstract: Adult T-cell leukemia/lymphoma (ATL) is an aggressive neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1). The HTLV-1 oncoprotein Tax plays an important role in ATL pathogenesis. ATL carries a poor prognosis due to chemotherapy resistance, stressing the need for alternative therapies. Here, we investigate the preclinical efficacy of the synthetic retinoid ST1926 in ATL and peripheral T-cell lymphomas. Clinically achievable concentrations of ST1926 induced a dramatic inhibition of cell proliferation in malignant T-cell lines and primary ATL cells with minimal effect on resting or activated normal lymphocytes. ST1926 induced apoptosis, DNA damage, and upregulation of p53 proteins in malignant T cells, whereas it caused an early downregulation of Tax proteins in HTLV-1-positive cells. In murine ATL, oral treatment with ST1926 prolonged survival and reduced leukemia cell infiltration, white blood cell counts, and spleen mass. In spleens of ST1926-treated animals, p53 and p21 proteins were upregulated, poly (ADP-ribose) polymerase was cleaved, and Tax transcripts were reduced. These results highlight the promising use of ST1926 as a targeted therapy for ATL.
authors.affiliation: Department of Internal Medicine, Department of Experimental Pathology, Microbiology and Immunology.
authors.forename: Hiba
authors.initials: H
authors.lastname: El Hajj
authors.affiliation: Department of Biology.
authors.forename: Bariaa
authors.initials: B
authors.lastname: Khalil
authors.affiliation: Department of Biochemistry and Molecular Genetics, and.
authors.forename: Botheina
authors.initials: B
authors.lastname: Ghandour
authors.affiliation: Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut, Lebanon;
authors.forename: Rihab
authors.initials: R
authors.lastname: Nasr
authors.affiliation: Department of Biology.
authors.forename: Sharif
authors.initials: S
authors.lastname: Shahine
authors.affiliation: Department of Biochemistry and Molecular Genetics, and.
authors.forename: Akram
authors.initials: A
authors.lastname: Ghantous
authors.affiliation: Department of Biochemistry and Molecular Genetics, and.
authors.forename: Rana
authors.initials: R
authors.lastname: Abdel-Samad
authors.affiliation: Department of Biology.
authors.forename: Ansam
authors.initials: A
authors.lastname: Sinjab
authors.affiliation: Department of Pathology, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo, Japan;
authors.forename: Hideki
authors.initials: H
authors.lastname: Hasegawa
authors.affiliation: Department of Pathology and Laboratory Medicine, American University of Beirut, Beirut, Lebanon;
authors.forename: Mark
authors.initials: M
authors.lastname: Jabbour
authors.affiliation: Centre for Research in Infectious Diseases, School of Medicine and Medical Science, University College Dublin, Dublin 4, Ireland;
authors.forename: William W
authors.initials: WW
authors.lastname: Hall
authors.affiliation: Department of Pathology and Laboratory Medicine, American University of Beirut, Beirut, Lebanon;
authors.forename: Ghazi
authors.initials: G
authors.lastname: Zaatari
authors.affiliation: Department of Biochemistry and Molecular Genetics, and Department of Pediatrics and Adolescent Medicine, American University of Beirut, Beirut, Lebanon; and.
authors.forename: Ghassan
authors.initials: G
authors.lastname: Dbaibo
authors.affiliation: Biogem, Research Institute, Ariano Irpino, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Pisano
authors.affiliation: Department of Internal Medicine, Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut, Lebanon;
authors.forename: Ali
authors.initials: A
authors.lastname: Bazarbachi
authors.affiliation: Department of Biochemistry and Molecular Genetics, and.
authors.forename: Nadine
authors.initials: N
authors.lastname: Darwiche
mesh_terms: D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002934:Cinnamates / Q000008:administration & dosage / Q000494:pharmacology*; D004249:DNA Damage; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D017254:Leukemic Infiltration; D051379:Mice; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C472791:3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid; D000970:Antineoplastic Agents; D002934:Cinnamates; D016356:Gene Products, tax; D016159:Tumor Suppressor Protein p53; D020169:Caspases; D000218:Adamantane