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. 2016 Aug 24;7(43):69945–69960. doi: 10.18632/oncotarget.11566

Figure 7. Bisindolylmaleimide IX was effective in treatment of leukemia-like disorders induced by BCR-ABL or T315I BCR-ABL.

Figure 7

A. Bisindolylmaleimide IX showed little effect on the size of tumors derived from HCT116 cells. The nude mice with tumor were treated with Bisindolylmaleimide IX, Itu, or solvent for different periods of time and the tumor size was measured every day. N=6. *p<0.05 when the tumor sizes with drug treatment were compared to those of untreated. B. Bisindolylmaleimide IX inhibited the growth of tumors derived from BCR-ABL-expressing BaF3 cells. The nude mice with tumor were treated with 4 mg/kg Bisindolylmaleimide IX or solvent for different periods of time and the tumor size was measured every day. The mean tumor volumes of treatment group were calculated at the final measurement, which were compared to that of vehicle-treated mice for statistical significance using Dunnett's test. N=8. *p<0.05 when the tumor sizes with drug treatment were compared to those of untreated. C. Bisindolylmaleimide IX inhibited the growth of tumors derived from T315I BCR-ABL-expressing BaF3 cells. The nude mice with tumor were treated with 4 mg/kg Bisindolylmaleimide IX or solvent for different periods of time and the tumor size was measured every day. The mean tumor volumes of treatment group were calculated at the final measurement, which were compared to that of vehicle-treated mice for statistical significance using Dunnett's test. N=8. *p<0.05 when the tumor sizes with drug treatment were compared to those of untreated at the same dose. D. Bisindolylmaleimide IX extended the lifespan of mice receiving BCR-ABL-expressing BaF3 cells. The nude mice were injected with BCR-ABL-expressing BaF3 cells. Three days later, these mice were treated with 2 or 4 mg/kg Bisindolylmaleimide IX or solvent every day and the lifespan of these mice were monitored. Each group contains 5 mice. E. Bisindolylmaleimide IX extended the lifespan of mice receiving T315I BCR-ABL-expressing BaF3 cells. The nude mice were injected with T315I BCR-ABL-expressing BaF3 cells. Three days later, these mice were treated with 2 or 4 mg/kg Bisindolylmaleimide IX or solvent every day and the lifespan of these mice were monitored. Each group contains 5 mice. F. Knockdown of B-Raf in BCR-ABL-expressing BaF3 cells with shRNA extended the lifespan of mice compared to control shRNA in response to Bisindolylmaleimide IX treatment. The nude mice were injected with BCR-ABL positive BaF3 cells that expressed control or B-Raf shRNA. Three days later, these mice were treated with 2 mg/kg Bisindolylmaleimide IX or solvent every day and the lifespan of these mice were monitored. Each group contains 7 mice. For B-Raf knockdown, see Supplementary results Figure S12. G. A diagram shows how Bisindolylmaleimide IX may treat CML. Bisindolylmaleimide IX inhibits DNA topoisomerases, which are down-regulated in BCR-ABL positive cells, to activate DDR and Atm-Chk2 to induce cell cycle arrest; and inhibits the Raf-Erk pathway, the BCR-ABL oncogene addiction pathway, to induce cell death.