title: Benzodithiophenes induce differentiation and apoptosis in human leukemia cells.
abstract: All-trans retinoic acid (ATRA) induces clinical remission in patients with t(15;17) acute promyelocytic leukemia (APL) carrying leukemogenic promyelocytic leukemia-retinoic acid receptor alpha (PML-RARalpha) fusion protein by overcoming PML-RARalpha transcriptional repression and inducing myeloid differentiation. To identify more potent chemical differentiation inducers, a screening assay was developed utilizing an ATRA-insensitive NB4 cell line (NB4-c) in which differentiation could be measured after 48 hours when primed with ATRA followed by other potential inducers. Over 300 cytostatic agents selected from the National Cancer Institute library were screened using this established method. Three compounds, NSC656243, NSC625748, and NSC144168, were identified to amplify ATRA-induced differentiation with acceptable cytotoxicity in NB4-c cells. In the absence of ATRA, these compounds also induced HL-60 and murine erythroleukemia cells to undergo partial differentiation. NSC656243, a benzodithiophene compound, was selected for further studies to examine the underlying mechanism of action. The differentiation effect of NSC656243 was associated with enhanced ATRA-mediated up-regulation of cell cycle regulatory proteins p21waf1 and p27kip1, retinoblastoma dephosphorylation, expression of RIG-E and RIG-G, and myelomonocytic differentiation-specific down-regulation of the myeloperoxidase (MPO) gene. Moreover, at 2- to 3-fold higher concentrations than those used to synergize with ATRA, NSC656243 induced apoptosis in NB4-c cells by reactive oxygen species-mediated pathways. The dual effects of benzodithiophenes (i.e., differentiation and apoptosis induction) support further development of these compounds as therapeutic agents for leukemia.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029-6547, USA.
authors.forename: Yongkui
authors.initials: Y
authors.lastname: Jing
authors.forename: Nella
authors.initials: N
authors.lastname: Hellinger
authors.forename: Lijuan
authors.initials: L
authors.lastname: Xia
authors.forename: Anne
authors.initials: A
authors.lastname: Monks
authors.forename: Edward A
authors.initials: EA
authors.lastname: Sausville
authors.forename: Arthur
authors.initials: A
authors.lastname: Zelent
authors.forename: Samuel
authors.initials: S
authors.lastname: Waxman
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects*; D019938:Cyclin D1 / Q000096:biosynthesis / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018922:HL-60 Cells; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy / Q000473:pathology; D007942:Leukemia, Experimental / Q000188:drug therapy* / Q000473:pathology; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D013876:Thiophenes; D019938:Cyclin D1; D014212:Tretinoin