Melatonin, a naturally occurring molecule, is produced by the pineal gland in a circadian manner to regulate biologic rhythms in humans. Recent studies report that melatonin may be an attractive candidate as an anticancer agent or for combined therapy because of its antioxidant, oncostatic and immunoregulatory activities. In this study, the potentiating effect of melatonin was evaluated on the apoptosis induced by puromycin as an anticancer drug in acute promyelocytic leukemia HL-60 cells. Melatonin did not show significant cytotoxicity against HL-60 cells compared to puromycin. However, melatonin significantly augmented the cytotoxicity of puromycin. Consistently, combined treatment of melatonin and puromycin reduced the expression of anti-apoptotic proteins, such as bcl-2 and bcl-xL, and also induced caspase-3 activation and poly (ADP-ribose) polymerase (PARP) cleavage compared to puromycin treatment alone. Furthermore, cell cycle analysis revealed that melatonin promoted puromycin-induced apoptosis by increasing the sub-G1 population, but suppressing G2/M arrest in HL-60 cells. Interestingly, melatonin activated the phosphorylation of 5′-adenosine monophosphate-activated kinase (AMPK) in combination with puromycin. Taken together, our results suggest that melatonin potentiates puromycin-induced apoptosis with caspase-3 and AMPK activation in HL-60 cells, and thus, melatonin treatment can be effectively applied to leukemia treatment as a potential sensitizer for chemotherapeutic agents. © 2011 John Wiley & Sons A/S.
5′-adenosine monophosphate-activated kinase-alpha; apoptosis; checkpoint kinase; HL-60 cells; melatonin; puromycin
EMTREE drug terms: 5' adenosine monophosphate activated kinase alpha; adenosine phosphate; caspase 3; checkpoint kinase 1; checkpoint kinase 2; melatonin; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; protein bcl 2; protein bcl xl; puromycin; unclassified drug
EMTREE medical terms: antineoplastic activity; apoptosis; article; cancer chemotherapy; cell cycle arrest; cell cycle G1 phase; cell cycle G2 phase; cell cycle M phase; cell strain HL 60; cell subpopulation; concentration response; controlled study; drug cytotoxicity; drug potentiation; drug structure; enzyme activation; human; human cell; promyelocytic leukemia; protein expression; protein phosphorylation
MeSH: AMP-Activated Protein Kinases; Apoptosis; Blotting, Western; Cell Cycle; HL-60 Cells; Humans; Melatonin; Puromycin
Medline is the source for the MeSH terms of this document.
Chemicals and CAS Registry Numbers: adenosine phosphate, 61-19-8, 8063-98-7; caspase 3, 169592-56-7; checkpoint kinase 2, 244634-79-5; melatonin, 73-31-4; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase, 58319-92-9; protein bcl 2, 219306-68-0; protein bcl xl, 151033-38-4; puromycin, 53-79-2, 58-58-2;AMP-Activated Protein Kinases, 126.96.36.199; Melatonin, 73-31-4; Puromycin, 53-79-2