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

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.

• Authors: 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
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 43 Pg. 69945-69960 (Oct 25 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27564101 (Publication Type: Journal Article)

Chemical References

• Indoles
• Maleimides
• Topoisomerase Inhibitors
• bisindolylmaleimide IX
• Fusion Proteins, bcr-abl
• BRAF protein, human
• Proto-Oncogene Proteins B-raf

Topics

• Animals
• Cell Cycle Checkpoints (drug effects)
• DNA Damage
• Drug Resistance, Neoplasm
• Fusion Proteins, bcr-abl (physiology)
• HCT116 Cells
• Humans
• Indoles (pharmacology, therapeutic use)
• K562 Cells
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, pathology)
• Male
• Maleimides (pharmacology, therapeutic use)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Proto-Oncogene Proteins B-raf (physiology)
• Topoisomerase Inhibitors (pharmacology)