3β-Acetyl tormentic acid reverts MRP1/ABCC1 mediated cancer resistance through modulation of intracellular levels of GSH and inhibition of GST activity

Mechanisms involved in sensitization of cancer cells by 3ATA. (1) By inhibiting the MRP1 activity, 3ATA increases the intracellular pool of drug allowing it to reach effective cytotoxic/lethal concentration. (2) This effect is also due to the ability of 3ATA in inhibiting GST activity and therefore, decreasing the amount of conjugated drug to be transported. (3) 3ATA decreases the intracellular pool of GSH contributing to limit the availability of cellular GSH needed for metabolizing and transporting some alkylating agents out of the cell. (4) By affecting/altering the GSH pool, 3ATA also decreases the antioxidant capacity of the cell, favors ROS accumulation. The overall result of these mechanisms is increased accumulation of drugs and cell death. 230