title: The synthetic retinoid ST1926 as a novel therapeutic agent in rhabdomyosarcoma.
abstract: Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma in children. Despite multiple attempts at intensifying chemotherapeutic approaches to treatment, only moderate improvements in survival have been made for patients with advanced disease. Retinoic acid is a differentiation agent that has shown some antitumor efficacy in RMS cells in vitro; however, the effects are of low magnitude. E-3-(4'-hydroxyl-3'-adamantylbiphenyl-4-yl) acrylic acid (ST1926) is a novel orally available synthetic atypical retinoid, shown to have more potent activity than retinoic acid in several types of cancer cells. We used in vitro and in vivo models of RMS to explore the efficacy of ST1926 as a possible therapeutic agent in this sarcoma. We found that ST1926 reduced RMS cell viability in all tested alveolar (ARMS) and embryonal (ERMS) RMS cell lines, at readily achievable micromolar concentrations in mice. ST1926 induced an early DNA damage response (DDR), which led to increase in apoptosis, in addition to S-phase cell cycle arrest and a reduction in protein levels of the cell cycle kinase CDK1. Effects were irrespective of TP53 mutational status. Interestingly, in ARMS cells, ST1926 treatment decreased PAX3-FOXO1 fusion oncoprotein levels, and this suppression occurred at a post-transcriptional level. In vivo, ST1926 was effective in inhibiting growth of ARMS and ERMS xenografts, and induced a prominent DDR. We conclude that ST1926 has preclinical efficacy against RMS, and should be further developed in this disease in clinical trials.
authors.affiliation: Children's Cancer Institute, American University of Beirut, Beirut, Lebanon.
authors.forename: Hussein
authors.initials: H
authors.lastname: Basma
authors.affiliation: Department of Biology, Faculty of Science, EDST, Lebanese University, Beirut, Lebanon.
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Ghayad
authors.affiliation: Department of Biology, Faculty of Science, EDST, Lebanese University, Beirut, Lebanon.
authors.forename: Ghina
authors.initials: G
authors.lastname: Rammal
authors.affiliation: Medicinal Investigational Research, Biogem Research Institute, Ariano Irpino, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Mancinelli
authors.affiliation: Children's Cancer Institute, American University of Beirut, Beirut, Lebanon.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Harajly
authors.affiliation: Children's Cancer Institute, American University of Beirut, Beirut, Lebanon.
authors.forename: Farah
authors.initials: F
authors.lastname: Ghamloush
authors.affiliation: Children's Cancer Institute, American University of Beirut, Beirut, Lebanon.
authors.forename: Loai
authors.initials: L
authors.lastname: Dweik
authors.affiliation: Department of Anatomy, Cell Biology and Physiology, American University of Beirut, Beirut, Lebanon.
authors.forename: Rabab
authors.initials: R
authors.lastname: El-Eit
authors.affiliation: Children's Cancer Institute, American University of Beirut, Beirut, Lebanon.
authors.forename: Hassan
authors.initials: H
authors.lastname: Zalzali
authors.affiliation: Children's Cancer Institute, American University of Beirut, Beirut, Lebanon.
authors.forename: Wissam
authors.initials: W
authors.lastname: Rabeh
authors.affiliation: Medicinal Investigational Research, Biogem Research Institute, Ariano Irpino, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Pisano
authors.affiliation: Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon.
authors.forename: Nadine
authors.initials: N
authors.lastname: Darwiche
authors.affiliation: Children's Cancer Institute, American University of Beirut, Beirut, Lebanon.|Department of Anatomy, Cell Biology and Physiology, American University of Beirut, Beirut, Lebanon.
authors.forename: Raya
authors.initials: R
authors.lastname: Saab
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002934:Cinnamates / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D064593:Heterografts; D006801:Humans; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D012208:Rhabdomyosarcoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C472791:3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid; D000970:Antineoplastic Agents; D002934:Cinnamates; D015514:Oncogene Proteins, Fusion; D016159:Tumor Suppressor Protein p53; D000218:Adamantane
keywords: DNA damage; PAX3-FOXO1; ST1926; cell cycle; retinoids; rhabdomyosarcoma