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.