title: Melatonin enhances hyperthermia-induced apoptotic cell death in human leukemia cells.
abstract: Melatonin is an endogenous indoleamine with a wide range of biological functions. In addition to modulating circadian rhythms, it plays important roles in the health as an antioxidant. Melatonin has also the ability to induce apoptosis in cancer cells and to enhance the antitumoral activity of chemotherapeutic agents. In this study, the effect of melatonin on hyperthermia-induced apoptosis was explored using human leukemia cells. The results demonstrate that melatonin greatly improved the cytotoxicity of hyperthermia in U937 cells. The potentiation of cell death was achieved with 1 mmol/L concentrations of the indoleamine but not with concentrations close to physiological levels in blood (1 nmol/L). This effect was associated to an enhancement of the apoptotic response, revealed by an increase in cells with hypodiploid DNA content and activation of multiple caspases (caspase-2, caspase-3, caspase-8, and caspase-9). Melatonin also increased hyperthermia-induced Bid activation as well as translocation of Bax from the cytosol to mitochondria and cytochrome c release. Hyperthermia-provoked apoptosis and potentiation by melatonin were abrogated by a broad-spectrum caspase inhibitor (z-VAD-fmk) as well as by specific inhibitors against caspase-8 or caspase-3. In contrast, blocking of the mitochondrial pathway of apoptosis either with a caspase-9 inhibitor or overexpressing the anti-apoptotic protein Bcl-2 (U937/Bcl-2) reduced the number of apoptotic cells in response to hyperthermia but it was unable to suppress melatonin enhancement. Melatonin appears to modulate the apoptotic response triggered by hyperthermia in a cell type-specific manner as similar results were observed in HL-60 but not in K562 or MOLT-3 cells.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Fisiología, Genética e Inmunología, Facultad de Ciencias de la Salud, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Quintana
authors.affiliation: Departamento de Ciencias Clínicas, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Cabrera
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Fisiología, Genética e Inmunología, Facultad de Ciencias de la Salud, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.
authors.forename: Juan
authors.identifier: http://orcid.org/0000-0002-0163-393X
authors.initials: J
authors.lastname: Perdomo
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Fisiología, Genética e Inmunología, Facultad de Ciencias de la Salud, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.|Instituto Universitario de Investigaciones Biomédicas y Sanitarias, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Estévez
authors.affiliation: Departamento de Ciencias Clínicas, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.|Instituto Universitario de Investigaciones Biomédicas y Sanitarias, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.
authors.forename: Juan F
authors.initials: JF
authors.lastname: Loro
authors.affiliation: Department of Cellular and Structural Biology, The University of Texas Health Science at San Antonio, San Antonio, TX, USA.
authors.forename: Russel J
authors.initials: RJ
authors.lastname: Reiter
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Fisiología, Genética e Inmunología, Facultad de Ciencias de la Salud, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain. jose.quintana@ulpgc.es.|Instituto Universitario de Investigaciones Biomédicas y Sanitarias, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain. jose.quintana@ulpgc.es.
authors.forename: José
authors.initials: J
authors.lastname: Quintana
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D007036:Hypothermia, Induced; D020014:K562 Cells; D007938:Leukemia / Q000378:metabolism* / Q000628:therapy*; D008550:Melatonin / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000378:metabolism; D020298:U937 Cells
chemical_list: D009363:Neoplasm Proteins; D020169:Caspases; D008550:Melatonin
keywords: apoptosis; caspases; hyperthermia; leukemia; melatonin