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An increasing number of studies indicate that melatonin protects normal cells, while it reducing cancer cell proliferation. In this study, we investigated the effect of melatonin on the growth of the human leukemia cells and found that it efficiently reduced the number of cells in a concentration\u2010 and time\u2010dependent manner. Thus, incubation with the indoleamine increased the percentage of cells with a hypodiploid <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> content, augmented the number of annexin V\u2013positive cells, and also provoked ultrastructural changes that are features of apoptotic cell death. Evaluation of caspases revealed that caspase\u20103, caspase\u20106, caspase\u20107, and caspase\u20109, but not caspase\u20108 and caspase\u20102, were quickly activated (3\u20136\u00a0hr). The increase in the activity of these proteases was associated with up\u2010regulation of the pro\u2010apoptotic factor Bax and also with the release of cytochrome <jats:italic>c<\/jats:italic> from mitochondria. Pretreatment of the cells with the general caspase inhibitor z\u2010<jats:styled-content style=\"fixed-case\">VAD<\/jats:styled-content>\u2010fmk, reduced melatonin\u2010induced apoptosis, but it did not block cell death suggesting that melatonin activates an alternative cell death modality in the absence of caspase activity. Thus, the activation of caspases was preceded by a fast (&lt;30\u00a0min) increase in reactive oxygen species (<jats:styled-content style=\"fixed-case\">ROS<\/jats:styled-content>). Rotenone and antimycin A reduced the levels of <jats:styled-content style=\"fixed-case\">ROS<\/jats:styled-content> stimulated by melatonin, indicating that the complex I and the complex <jats:styled-content style=\"fixed-case\">III<\/jats:styled-content> of the mitochondrial electron transport chain are important sources of these chemical species. However, the role of <jats:styled-content style=\"fixed-case\">ROS<\/jats:styled-content> in melatonin\u2010induced cell death remains elusive because anti\u2010oxidants that were shown to decrease <jats:styled-content style=\"fixed-case\">ROS<\/jats:styled-content> levels (glutathione, <jats:italic>N<\/jats:italic>\u2010acetyl\u2010<jats:sc>l<\/jats:sc>\u2010cysteine and Trolox) were unable to abrogate melatonin\u2010induced cell death.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jpi.12062","type":"journal-article","created":{"date-parts":[[2013,4,30]],"date-time":"2013-04-30T15:57:39Z","timestamp":1367337459000},"page":"195-206","source":"Crossref","is-referenced-by-count":52,"title":["Melatonin induces apoptosis through a caspase\u2010dependent but reactive oxygen species\u2010independent mechanism in human leukemia Molt\u20103 cells"],"prefix":"10.1111","volume":"55","author":[{"given":"Juan","family":"Perdomo","sequence":"first","affiliation":[{"name":"Departamento de Bioqu\u00edmica y 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(ICIC) Canary Islands Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"Loro","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Cl\u00ednicas Facultad de Ciencias de la Salud Universidad de Las Palmas de Gran Canaria Las Palmas de Gran Canaria Spain"},{"name":"Instituto Canario de Investigaci\u00f3n del C\u00e1ncer (ICIC) Canary Islands Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Russel J.","family":"Reiter","sequence":"additional","affiliation":[{"name":"Department of Cellular and Structural Biology University of Texas Health Science Center San Antonio TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9","family":"Quintana","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular, Fisiolog\u00eda, Gen\u00e9tica e Inmunolog\u00eda Facultad de Ciencias de la Salud Universidad de Las Palmas de Gran Canaria Las Palmas de Gran 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