Melatonin induces mitochondrial‐mediated apoptosis in human myeloid HL‐60 cells

Abstract

The role of melatonin in the mediation of apoptotic events has recently gained attention, especially after recent studies have reported that melatonin exerts antiapoptotic actions in normal cells but may activate proapoptotic pathways in some tumor cells. Here, we have evaluated the effect of melatonin on apoptosis in the human leukemia cell line HL-60. Melatonin treatment (1 mm) induced a significant increase in caspase-3 and -9 activities. The effect of melatonin on the activation of caspases was time dependent, reaching a maximum after 12 hr of stimulation, and then decreasing to a minimum after 72 hr. Treatment with melatonin also evoked mitochondrial membrane depolarization and permeability transition pore induction, which caused loss of mitochondrial staining by calcein, and increased cell death by apoptosis/necrosis as demonstrated by propidium iodide positive-staining of cells after 72 hr of stimulation. In addition, the exposure of cells to melatonin resulted in an activation and association of the proapoptotic proteins Bax and Bid, as well as promoting detectable increases in the expression of both proteins. We conclude that melatonin has proapoptotic and/or oncostatic effects in the human myeloid cell line HL-60.

Interactions of melatonin with mammalian mitochondria. Reducer of energy capacity and amplifier of permeability transition

“…The authors suggest the same mechanism proposed for RHM (see above), i.e., that melatonin protects by scavenging hydroxyl and peroxyl radicals responsible for the oxidative stress leading to apoptosis (Espino et al 2010). Another recent paper reports that, in human myeloid HL-60 cells, melatonin induces caspase activation accompanied by mitochondrial depolarization, induction of MPT, release of cytochrome C, and apoptosis (Bejarano et al 2009). These findings match our results in RLM, although the authors do not report any effect regarding possible oxidative stress induced by melatonin.…”

“…It has also been found that the indolamine induces mitochondrial-mediated apoptosis in human myeloid HL-60 cells (Bejarano et al 2009) but reduces this process in human leukocytes (Espino et al 2010). The differential actions exhibited by melatonin on mitochondria and apoptosis in normal and cancer cells were also previously reported in a review article (Sainz et al 2003).…”

Melatonin-Induced Oncostasis, Mechanisms and Clinical Relevance

“…The intrinsic and extrinsic pathways are connected by the caspase-8-mediated cleavage of the pro-apoptotic Bcl-2 family member BH3 interacting-domain death agonist (Bid), which translocates to mitochondria to trigger the release of cytochrome C. Melatonin increases the activation and association of Bax and Bid and is associated with a detectable rise in the expression of both proteins [11,49]. For example, melatonin upregulates Bax and the conversion of caspase-3 to cleaved form in human colorectal cancer cells [15].…”

Melatonin as a stabilizer of mitochondrial function: role in diseases and aging

“…In this sense, melatonin seems to be able to block ETC complexes and decrease ATP production (Wang et al, 2013), as well as activate the intrinsic apoptotic pathway (Bejarano et al, 2009). Furthermore, antioxidant and scavenger capacities of melatonin may also intervene (Espino et al, 2010;Luchetti et al, 2010).…”