Selumetinib Inhibits T-Acute Lymphoblastic Leukemia Cell Proliferation by Inducing Apoptosis, Inhibiting Autophagy, and Modulating Reactive Oxygen Species Pathway.

BACKGROUND

Early relapse and a poor prognosis are standard features of T-acute lymphoblastic leukemia (T-ALL), a hematological malignancy that presents significant treatment challenges. Glucocorticoids (GCs) are the first line of treatment for T-ALL; nevertheless, GC resistance may develop in patients with newly diagnosed and recurrent T-ALL due to abnormalities in apoptotic pathways. Here, we investigated the impact of the targeted medication, selumetinib, on the expression of proteins that regulate apoptosis in malignant T-ALL cells. We examined the Bcl-2, Bax, P53, Beclin1, and NFE2L2 expression levels as proteins directly or indirectly regulating the apoptosis pathway.

MATERIALS AND

METHODS

Jurkat cells were treated with different concentrations of selumetinib. Cell viability and IC50 values were measured using the Alamar Blue assay. Gene expression profiles of Bcl-2, Bax, P53, Beclin1, and NFE2L2 were assessed using real-time PCR.

RESULTS

The results revealed that selumetinib significantly increased P53, Bax gene expression (P < 0.05), and Bax/Bcl-2 ratio in a time- and dose-dependent manner. A significant decrease was also observed in Beclin1 and NFE2L2 expression (P < 0.05).

CONCLUSION

The study presented here showed that selumetinib at higher doses induced Bax and P53 expression levels and did not affect Bcl-2 in Jurkat cells. This suggests that selumetinib may significantly induce apoptosis in apoptosis-defective T-ALL cells. Moreover, at lower doses, by reducing the expression of Beclin1 and NFE2L2, selumetinib may inhibit the autophagy-dependent survival pathway and induce apoptosis through increasing ROS in patients with newly diagnosed or relapsed ALL, respectively.