Identification of Bisindolylmaleimide IX as a potential agent to treat drug-resistant BCR-ABL positive leukemia

Xin Zhang, Deyong Jia, Junping Ao, Huijuan Liu, Yi Zang, Mohammad Azam, Samy L. Habib, Jia Li, Xinsen Ruan, Hao Jia, Xueying Wang, Baojie Li

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Chronic myeloid leukemia (CML) treatment with BCR-ABL inhibitors is often hampered by development of drug resistance. In a screen for novel chemotherapeutic drug candidates with genotoxic activity, we identified a bisindolylmaleimide derivative, IX, as a small molecule compound with therapeutic potential against CML including drug-resistant CML. We show that Bisindolylmaleimide IX inhibits DNA topoisomerase, generates DNA breaks, activates the Atm-p53 and Atm-Chk2 pathways, and induces cell cycle arrest and cell death. Interestingly, Bisindolylmaleimide IX is highly effective in targeting cells positive for BCR-ABL. BCR-ABL positive cells display enhanced DNA damage and increased cell cycle arrest in response to Bisindolylmaleimide IX due to decreased expression of topoisomerases. Cells positive for BCR-ABL or drug-resistant T315I BCR-ABL also display increased cytotoxicity since Bisindolylmaleimide IX inhibits B-Raf and the downstream oncogene addiction pathway. Mouse cancer model experiments showed that Bisindolylmaleimide IX, at doses that show little side effect, was effective in treating leukemia-like disorders induced by BCR-ABL or T315I BCR-ABL, and prolonged the lifespan of these model mice. Thus, Bisindolylmaleimide IX presents a novel drug candidate to treat drug-resistant CML via activating BCR-ABL-dependent genotoxic stress response and inhibiting the oncogene addiction pathway activated by BCR-ABL.

Original languageEnglish (US)
Pages (from-to)69945-69960
Number of pages16
JournalOncotarget
Volume7
Issue number43
DOIs
StatePublished - 2016

Keywords

  • BCR-ABL
  • Bisindolylmaleimide IX
  • Chronic myeloid leukemia (CML)

ASJC Scopus subject areas

  • Oncology

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