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J Pineal Res. 2016 Oct;61(3):381-95. doi: 10.1111/jpi.12356. Epub 2016 Aug 13.

Melatonin enhances hyperthermia-induced apoptotic cell death in human leukemia cells.

Author information

1
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.
2
Departamento de Ciencias Clínicas, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.
3
Instituto Universitario de Investigaciones Biomédicas y Sanitarias, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.
4
Department of Cellular and Structural Biology, The University of Texas Health Science at San Antonio, San Antonio, TX, USA.
5
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.
6
Instituto Universitario de Investigaciones Biomédicas y Sanitarias, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain. jose.quintana@ulpgc.es.

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.

KEYWORDS:

apoptosis; caspases; hyperthermia; leukemia; melatonin

PMID:
27465521
DOI:
10.1111/jpi.12356
[Indexed for MEDLINE]

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