Melatonin enhances the effect of ABT-737 in acute monocytic leukemia THP-1 cells

Abstract

Melatonin (N-acetyl-5-methoxytryptamine, MEL) is a hormone synthesized by the pineal gland. Due to its oncostatic effect, it can be considered as an antitumor agent and used for combination therapy. ABT-737, a Bcl-2 inhibitor, promotes cell death after treatment with agents that induce pro-apoptotic signals. In the present study, the combined effect of MEL and ABT-737 on changes in proliferative and mitotic activity, mitochondrial membrane potential, intracellular production of reactive oxygen species (ROS) and cytosolic Ca2+ was studied. Moreover, changes in the expression of anti- and pro-apoptotic proteins (Bcl-2 and Bax), autophagy markers (LC3A/B (I, II)), endoplasmic reticulum stress markers (chaperones BIP and PDI, CHOP) were studied under these conditions. The effect of MEL together with ABT-737 led to an increase in the level of cytosolic Ca2+, intracellular production of ROS, and a decrease in the membrane potential of mitochondria. Under these conditions, the content of Bcl-2 increased, while the level of Bax decreased. The activation of CHOP stimulated autophagy and led to a decrease in the expression of BIP and PDI chaperones. These results suggest that MEL is able to enhance the effects of other chemotherapeutic agents and can be used in strategies in the treatment of cancer.