Anti-leukemia effects of the novel synthetic 1-benzylindole derivative 21-900 in vitro and in vivo.

Cancers are the major cause of death worldwide. Chemotherapy using cytotoxic drugs and targeted therapy is required when surgery is difficult, ineffective, or impossible. We previously synthesized the novel synthetic 1-benzylindole derivative 21-900 and found that it inhibits histone deacetylase (HDAC) activities and tubulin assembly. Here we tested its effects on the human leukaemia cell lines HL-60 and MOLT-4 in vitro and in vivo. We found that its potent cytotoxic effects were mediated through cell cycle arrest at the G2/M phase, which increased the population of sub-G1 cells, leading to apoptosis. Further, tubulin was depolymerized by 21-900 in a manner similar to that of vincristine, leading to disruption of microtubule dynamics and increased levels of the mitotic marker MPM-2. Further, 21-900 increased the expression of cleavage form of poly (ADP-ribose) polymerase (PARP), caspase 3, 7 (cleavage form), and pro-apoptotic protein BAK and decreased the expression of pro-survival BCL-2-family proteins BCL-2, MCL-1, and BID pro-form, leading to the induction of apoptosis. The growth of tumours in nude mice formed by xenografts of HL-60 and MOLT-4 cells was significantly inhibited by 21-900 without causing the mice to lose body weight. These findings indicate that 21-900 may serve as a potent anti-leukaemia drug.