Melatonin provokes cell death in human B‐lymphoma cells by mitochondrial‐dependent apoptotic pathway activation

Abstract

Apoptosis is an important cell suicide programme involved in physiological and pathological processes. Apoptosis can be induced in different ways depending on cell type and acquired signal. Melatonin, the major secretory product of the pineal gland, participates in many important physiological functions and displays a remarkable functional versatility exhibiting antioxidant, oncostatic, anti-aging, and immunomodulatory properties. Recently, it has been shown that, in addition to pineal gland, human lymphoid cells are an important physiological source of melatonin and that may be involved in the regulation of the immune system. In this work, we examine the effect of melatonin on RAMOS-1 human leukaemic cells. Cell growth and viability, DNA fragmentation and JC-1, and annexin V expression have been determined. To elucidate the mechanism of action of melatonin, Western blot analyses for Bcl-2 and caspase-3 expression, and cytochrome c release were carried out. The results suggest that the apoptotic effect of melatonin is associated with cell-cycle arrest, downregulation of Bcl-2, mitochondrial membrane depolarization, cytochrome c release and activation of caspase-3. The intrinsic (mitochondrial dependent) pathway of caspase activation is the 'point of no return' commitment to cell death. Taken together, our study indicates that melatonin may play a role as potential therapeutic drug in specific lymphoproliferative diseases.

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

“…Although our results were unable to demonstrate a real effect of Mel in the downregulation of Bcl-2, there was a profound reduction in survivin expression following either Mel therapy or EtOH intake. It has been extensively studied the role of high concentrations of Mel in determining the proapoptotic actions related to early oxidative stress in tumor cells (Trubiani et al 2005, Rubio et al 2007). For example, Trubiani et al (2005) described activation of caspase-3 and cytochrome c, and a decrease in the levels of Bcl-2 after treatment with 2 mM Mel in lymphoma cell Immunohistochemical localization and western blot analysis of Bcl-2 and survivin in serous papillary OC.…”

Melatonin-Induced Oncostasis, Mechanisms and Clinical Relevance

“…Other studies have shown the release of pro-apoptotic agents from mitochondria, triggered by melatonin in tumor cells [10,24]. The mechanisms of melatonin's induction of apoptosis include mitochondrial membrane depolarization and permeability transition pore induction, which strongly suggests involvement of the mitochondrial-mediated pathway of apoptosis.…”

“…For example, melatonin upregulates Bax and the conversion of caspase-3 to cleaved form in human colorectal cancer cells [15]. Melatonin also promotes Bcl-2 down-regulation [10], suggesting that it may be an important endogenous cell death modulator. Moreover, melatonin synergistically promotes chemotherapy-induced apoptosis, mainly through downregulation of Bcl2 and elevation of pro-apoptotic proteins.…”

Prooxidant effects of melatonin: a brief review

“…Some experimental models of tissue damage demonstrate that melatonin acts protectively by reducing oxidative stress and lipid peroxidation (Pieri et al, 1995;Reiter et al, 1998). Furthermore, melatonin exerts anticancer activities through either cytostatic mechanisms or cytotoxic actions by inhibiting cell proliferation and/or reducing viability in several cancer cell lines, including rat pancreatic tumor cells (Gonzalez et al, 2011), human hepatocellular carcinoma cells (Ordoñez et al, 2014), human B-lymphoma cells (Trubiani et al, 2005), human myeloid HL-60 leukemia cells (Rubio et al, 2007), and human neuroblastoma cancer cells (Garcia-Santos et al, 2006).…”