Melatonin induces apoptosis through a caspase‐dependent but reactive oxygen species‐independent mechanism in human leukemia Molt‐3 cells

Abstract

Melatonin is a naturally occurring indoleamine synthesized in the pineal gland that exhibits an extensive repertoire of biological activities. 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- and time-dependent manner. Thus, incubation with the indoleamine increased the percentage of cells with a hypodiploid DNA content, augmented the number of annexin V-positive cells, and also provoked ultrastructural changes that are features of apoptotic cell death. Evaluation of caspases revealed that caspase-3, caspase-6, caspase-7, and caspase-9, but not caspase-8 and caspase-2, were quickly activated (3-6 hr). The increase in the activity of these proteases was associated with up-regulation of the pro-apoptotic factor Bax and also with the release of cytochrome c from mitochondria. Pretreatment of the cells with the general caspase inhibitor z-VAD-fmk, reduced melatonin-induced 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 (<30 min) increase in reactive oxygen species (ROS). Rotenone and antimycin A reduced the levels of ROS stimulated by melatonin, indicating that the complex I and the complex III of the mitochondrial electron transport chain are important sources of these chemical species. However, the role of ROS in melatonin-induced cell death remains elusive because anti-oxidants that were shown to decrease ROS levels (glutathione, N-acetyl-l-cysteine and Trolox) were unable to abrogate melatonin-induced cell death.

Melatonin Prevents Chemical-Induced Haemopoietic Cell Death

“…However, studies based on the activity of MEL on cell cultures give a completely different picture of its effect, describing an intense pro-oxidant activity of the hormone in certain conditions [11–13]. High concentrations of MEL (more than 100 μM) enhance the effect of chemotherapeutic drugs, both in cultured cancer cells [14–19] and in vivo [20,21], suggesting that in particular conditions MEL can be harmful, if not deleterious, for cancer cells.…”

Melatonin and ubiquitin: what’s the connection?

“…We have already documented the inhibitory action of melatonin on nf-κB and the role of the proteasome in activating nf-κB. Melatonin can also induce accumulation of the tumor suppressor factor p53 [101], of the stress-related enzyme JnK [102], and of the pro-apoptotic proteins Bax and caspase-3 [103] in cancer cells. It decreases the activity of the protein kinase, aKt [104], decreases the activity of the angiogenic factor, VeGf [105], and activates the transcription factor nrf-2 [106].…”

Apoptosis is triggered by melatonin in an in vivo model of ovarian carcinoma

“…Mel has been described as a molecule with remarkable pro-apoptotic activity in many tumor types, such as Ehrlich tumor, colorectal, breast, and liver (Cos et al 2002, Batista et al 2013, Fan et al 2013, Hong et al 2014. Activities of Mel on such tumors include modulation of BAX and Bcl-2 (Hong et al 2014), p53 and p21 (Cos et al 2002), and further regulation of caspase-3 with the release of cytochrome c (Perdomo et al 2013). Most reports on the apoptotic effect of Mel to cancer cells are focused on oxidative stress (Rodriguez et al 2013), and no study was conducted to test the efficacy of Mel therapy on OC regarding the apoptosis signaling molecules.…”