Abstract
T-cell acute lymphoblastic leukemia is an aggressive hematologic malignancy which is usually associated with unfavorable prognosis particularly in patients with refractory/relapsed disease. Therefore, development of novel therapeutic strategies is highly required for improving the outcome of these patients. Although there are several studies evaluating the efficacy of proteasome inhibitors on acute lymphoblastic leukemia of B-cell lineage, the data are still limited regarding T-cell acute lymphoblastic leukemia. Here, we tried to investigate the effects of the proteasome inhibition by carfilzomib on the induction of apoptosis and autophagy in Molt4 cells. The effect of carfilzomib in combination with dexamethasone in Molt4, as a glucocorticoid-resistant T-cell acute lymphoblastic leukemia cell line, was also assessed. Our data showed that carfilzomib can induce both apoptosis and autophagy in Molt4 cells. Furthermore, we found that carfilzomib is a potent inducer of reactive oxygen species production and also induces G2/M phase cell cycle arrest in Molt4 cells. Concomitant treatment with carfilzomib and dexamethasone demonstrated that carfilzomib can synergistically enhance the cytotoxic effect of dexamethasone on Molt4 cells. Furthermore, co-treatment of the cells with carfilzomib and dexamethasone increased the induction of autophagy as compared with each drug alone. In conclusion, our results are suggestive of the effectiveness of carfilzomib on Molt4 cells as a model of GC-resistant T-cell acute lymphoblastic leukemia.