Proteasome Inhibition by Carfilzomib Induced Apotosis and Autophagy in a T-cell Acute Lymphoblastic Leukemia Cell Line

Document Type: Research article

Authors

1 Department of Laboratory Hematology and Blood Bank, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

2 HSCT Research Center, Department of Laboratory Hematology and Blood Bank, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

3 Department of Medical Lab Technology, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

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.

Keywords

Main Subjects