Benzodithiophenes induce differentiation and apoptosis in human leukemia cells

Yongkui Jing, Nella Hellinger, Lijuan Xia, Anne Monks, Edward A. Sausville, Arthur Zelent, Samuel Waxman

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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 α (PML-RARα) fusion protein by overcoming PML-RARα 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.

Original languageEnglish
Pages (from-to)7847-7855
Number of pages9
JournalCancer Research
Issue number17
StatePublished - 1 Sep 2005


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