Combination of bortezomib and daunorubicin in the induction of apoptosis in T-cell acute lymphoblastic leukemia.

Abstract

Despite advances in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), the outcome of T-ALL treatment remains unsatisfactory, therefore, more effective treatment is urgently required. The present study examined the cytotoxicities of bortezomib in combination with daunorubicin against human Jurkat and Molt-4 T-ALL cells and primary T-ALL cells. Compared with treatment alone, co-exposure of cells to bortezomib and daunorubicin resulted in a significant increase in cell death in the Jurkat cells, as evidenced by the increased percentage of Annexin V-positive cells, the formation of apoptotic bodies. In addition, the administration sequence of bortezomib and daunorubicin had an effect on cell viability. Treatment with bortezomib followed by daunorubicin treatment was more effective, compared with treatment with daunorubicin followed by bortezomib. Co-treatment with bortezomib and daunorubicin markedly enhanced the activation of caspase-3, -8 and -9, which was reversed by the pan-caspase inhibitor, Z-VAD-FMK. In addition, cotreatment with bortezomib and daunorubicin enhanced the collapse of mitochondrial transmembrane potential and upregulated the proapoptotic protein, B-cell lymphoma 2 (Bcl-2)-interacting mediator of cell death (Bim), but not Bcl-2 or Bcl-extra large. Consistent with this, it was demonstrated that cotreatment of bortezomib and daunorubicin efficiently induced apoptosis in primary T-ALL cells, and cell death was associated with the collapse of mitochondrial transmembrane potential and the upregulation of Bim. Taken together, these findings indicated that the combination of bortezomib and daunorubicin significantly enhanced their apoptosis-inducing effect in T-ALL cells, which may warrant further investigation in preclinical and clinical investigations.