title: ST1926, an orally active synthetic retinoid, induces apoptosis in chronic myeloid leukemia cells and prolongs survival in a murine model.
abstract: The tyrosine kinase inhibitor, imatinib, is the first line of treatment for chronic myeloid leukemia (CML) patients. Unfortunately, patients develop resistance and relapse due to bcr-abl point mutations and the persistence of leukemia initiating cells (LIC). Retinoids regulate vital biological processes such as cellular proliferation, apoptosis, and differentiation, in particular of hematopoietic progenitor cells. The clinical usage of natural retinoids is hindered by acquired resistance and undesirable side effects. However, bioavailable and less toxic synthetic retinoids, such as the atypical adamantyl retinoid ST1926, have been developed and tested in cancer clinical trials. We investigated the preclinical efficacy of the synthetic retinoid ST1926 using human CML cell lines and the murine bone marrow transduction/transplantation CML model. In vitro, ST1926 induced irreversible growth inhibition, cell cycle arrest and apoptosis through the dissipation of the mitochondrial membrane potential and caspase activation. Furthermore, ST1926 induced DNA damage and downregulated BCR-ABL. Most importantly, oral treatment with ST1926 significantly prolonged the longevity of primary CML mice, and reduced tumor burden. However, ST1926 did not eradicate LIC, evident by the ability of splenocytes isolated from treated primary mice to develop CML in untreated secondary recipients. These results support a potential therapeutic use of ST1926 in CML targeted therapy.
authors.affiliation: Department of Anatomy, Cell Biology, and Physiological Sciences, American University of Beirut, Beirut, Lebanon.
authors.forename: Rihab R
authors.initials: RR
authors.lastname: Nasr
authors.affiliation: Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon.
authors.forename: Raed A
authors.initials: RA
authors.lastname: Hmadi
authors.affiliation: Department of Anatomy, Cell Biology, and Physiological Sciences, American University of Beirut, Beirut, Lebanon.
authors.forename: Rabab M
authors.initials: RM
authors.lastname: El-Eit
authors.affiliation: Department of Anatomy, Cell Biology, and Physiological Sciences, American University of Beirut, Beirut, Lebanon.
authors.forename: Ahmad N
authors.initials: AN
authors.lastname: Iskandarani
authors.affiliation: Department of Pathology and Laboratory Medicine, American University of Beirut, Beirut, Lebanon.
authors.forename: Mark N
authors.initials: MN
authors.lastname: Jabbour
authors.affiliation: Department of Pathology and Laboratory Medicine, American University of Beirut, Beirut, Lebanon.
authors.forename: Ghazi S
authors.initials: GS
authors.lastname: Zaatari
authors.affiliation: Laboratoire D'hématologie Et Service Des Maladies Du Sang, CHU De Bordeaux, Université Victor Ségalen Bordeaux 2, INSERM U876, Bordeaux, France.
authors.forename: Francois-Xavier
authors.initials: FX
authors.lastname: Mahon
authors.affiliation: BIOGEM, Medicinal Investigational Research, Ariano Irpino (AV), Italy.
authors.forename: Claudio C P
authors.initials: CC
authors.lastname: Pisano
authors.affiliation: Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon.
authors.forename: Nadine D
authors.initials: ND
authors.lastname: Darwiche
mesh_terms: D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000284:Administration, Oral; 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; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002934:Cinnamates / Q000008:administration & dosage / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D017382:Reactive Oxygen Species / Q000378:metabolism; D012176:Retinoids / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C472791:3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid; D000970:Antineoplastic Agents; D002934:Cinnamates; D017382:Reactive Oxygen Species; D012176:Retinoids; D016044:Fusion Proteins, bcr-abl; D020169:Caspases; D000218:Adamantane
keywords: BCR-ABL; ST1926; apoptosis; chronic myeloid leukemia; leukemia initiating cells; retinoids