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.
Highlights
Cancer is a leading cause of mortality worldwide and can be treated with radiotherapy and/or chemotherapy [1]
We have reported that 5-Iodotubercidin, as a nucleoside analog that can be incorporated into DNA and cause DNA damage, is effective in treating mouse embryonic fibroblasts (MEFs) or HCT116-induced tumors in mouse models [31]
We found that all the other PKC inhibitors in the kinase inhibitor panel including GF109203X (Bisindolylmaleimide I), H-7, H-9, staurosporine, Hypericin, Rottlerin, Sphingosine, Palmitoyl-DLcarnitine Cl, HBDDE (2,2′,3,3′,4,4′-Hexahydroxy-1,1biphenyl-6,6′-dimethanol Dimethyl Ether) failed to upregulate p53 in MEFs, suggesting that PKC kinases may not be the main reason behind p53 induction elicited by Bisindolylmaleimide IX
Summary
Cancer is a leading cause of mortality worldwide and can be treated with radiotherapy and/or chemotherapy [1]. An ABL kinase inhibitor, is effective for initial treatment of CML, yet a large percentile of CML patients gradually develop resistance [7], due to mutations in BCR-ABL, e.g., T315I, which disrupt imatinib-BCR-ABL interaction [8]. The occurrence of these mutations is driven by BCR-ABL itself, as BCRABL promotes DNA damage via reactive oxygen species (ROS)-dependent and -independent mechanisms [9,10,11], and affects multiple DNA repair processes [12, 13]. New drugs that can overcome the resistance are needed to combat CML [15,16,17]
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