Repurposing Verapamil to Enhance Killing of T-ALL Cells by the mTOR Inhibitor Everolimus

Area of Science:

• Oncology
• Pharmacology
• Cell Biology

Background:

• Standard chemotherapy is ineffective for some T-cell acute lymphoblastic leukemia (T-ALL) patients.
• Everolimus, an mTORC1 inhibitor, increases reactive oxygen species (ROS) and induces apoptosis in T-ALL cells.
• Everolimus has previously shown to improve dexamethasone response in T-ALL models.

Purpose of the Study:

• To investigate the efficacy of verapamil in combination with everolimus for T-ALL treatment.
• To evaluate the synergistic effects of verapamil and everolimus on T-ALL cell death and key molecular pathways.
• To assess the in vivo efficacy of the verapamil-everolimus-dexamethasone combination in refractory T-ALL models.

Main Methods:

• T-ALL cell lines and patient-derived xenografts (PDX) were used.
• Effects of everolimus and verapamil on ROS, cell death, glucose-6-phosphate dehydrogenase (G6PD), and p38 MAPK phosphorylation were assessed.
• In vivo studies were conducted in NOD/SCID mice inoculated with refractory T-ALL PDX cells.

Main Results:

• Verapamil synergistically enhanced everolimus-induced ROS production and cell death in T-ALL cells.
• The combination significantly reduced G6PD levels and increased p38 MAPK phosphorylation.
• In vivo, verapamil addition to everolimus plus dexamethasone markedly reduced tumor growth in refractory T-ALL PDX models.

Conclusions:

• Verapamil potentiates the anti-leukemic effects of everolimus in T-ALL.
• The combination therapy targets critical pathways including ROS, G6PD, and p38 MAPK.
• Repurposing verapamil with mTORC inhibitors and glucocorticoids offers a potential therapeutic strategy for refractory T-ALL.