Fig. 8: Proposed mechanism for the CBD effect on T-ALL cells.

Highly lipophilic CBD readily permeates plasma membrane and enters the cytosol, approaching mitochondria. Direct CBD interaction with VDAC favors the channel closed substate with increased Ca²⁺ permeability. It favors mitochondrial Ca²⁺ uptake through VDAC and MCU, leading to the mitochondrial Ca²⁺ overload that promotes the mPTP formation, Δψm loss, mitochondrial swelling, and cristae disruption. mPTP opening promotes the Cyt-C release from mitochondria. In cytoplasm, Cyt-C may orchestrate the apoptosome formation, caspases´ activation, and triggers the intrinsic apoptosis. mPTP rapidly triggers Ca²⁺ release from the ER, which tends to promote the mitochondrial Ca²⁺ overload in a feedforward manner. The CBD-induced dysfunction of mitochondria is accompanied by severe oxidative stress and rapid loss of ATP production, resulting in the MPT-driven necrosis. Autophagy occurs in T-ALL cells treated with sublethal CBD concentrations