Intracellular Signaling Pathways Involved in the Cell Growth Inhibition of Glioma Cells by Melatonin

Abstract

Melatonin is an indolamine mostly produced in the pineal gland, soluble in water, and highly lipophilic, which allows it to readily cross the blood-brain barrier. Melatonin possesses antioxidant properties and its long-term administration in rodents has not been found to cause noteworthy side effects. In the present work, we found that millimolar concentrations of this indolamine reduced cell growth of C6 glioma cells by 70% after 72 hours of treatment, inhibiting cell progression from G 1 to S phase of the cell cycle. Intraperitoneal administration of 15 mg/kg body weight of melatonin to rats previously injected in the flank with C6 glioma cells reduces tumor growth by 50% 2 weeks after the implant. Inhibition of cell growth does not depend on melatonin membrane receptor activation whereas it seemingly relates to the reduction of intracellular basal free radical levels by 30%. Increase of basal redox state of the cells and constitutive activation of tyrosine kinase receptor [receptor tyrosine kinase (RTK)] pathways, including the extracellular signal-regulated kinase 1/2 (ERK1/2) and the Akt and protein kinase C (PKC) signaling pathways, contribute to the progression of the gliomas leading to the constitutive activation of the redox-dependent survival transcription factor nuclear factor KB (NF-KB). The antioxidant effect of melatonin in C6 cells is associated to inhibition of NF-KB and Akt, but not of ERK1/2. The antiproliferative effect of the indolamine on these cells is partially abolished when coincubated with the PKC activator 12-O-tetradecanoylphorbol-13-acetate, thus indicating that the ability of melatonin to change cellular redox state may be inactivating the pathway RTK/PKC/ Akt/NF-KB. (Cancer Res 2006; 66(2): 1081-8)

A Review of Melatonin, Its Receptors and Drugs

“…Neurological disorders which have been reported to be improved by administration of melatonin are as follows: Parkinsonism [10], Alzheimer's disease [11], brain edema and traumatic brain injury [12], alcoholism [13], depression [14], cerebral ischemia [15], hyperhomocysteinuria [16], glioma [17] and phenylketonuria [18]. Alzheimer's disease is an age-related progressive neurodegenerative disorder, characterized with loss of cognitive functions, dementia and other neurobiological findings [2,19].…”

Inhibitory effects of pharmacological doses of melatonin on aromatase activity and expression in rat glioma cells

“…Melatonin has been shown to have neuroprotective effects in a large number of different experimental models (Cos et al, 1996;Armstrong and Niles, 2002;Feng and Zhang, 2004;Rincón Castro et al, 2005;Martín et al, 2006;Herrera et al, 2007). However, there is limited evidence suggesting that melatonin may affect glioblastoma growth.…”

Inhibitory effects of melatonin on sulfatase and 17β-hydroxysteroid dehydrogenase activity and expression in glioma cells

“…It has been also reported that melatonin at millimolar concentrations reduces, both in vitro and in vivo, the growth of C6 glioma cells (26,30). This inhibition has been related to reduced intracellular peroxides and a subsequent inhibition of the activity of important intracellular effectors, such as Akt and nuclear factor (NF)-κB and protein kinase C (26,30). In addition to the beneficial effects of providing direct antioxidant protection to glioma cells, melatonin may enhance neuroprotection against Aß-induced neurotoxicity by attenuating Aß25-35 or Aß1-42-induced apoptosis and promoting the survival of glial cells (24).…”

“…Melatonin has been shown to have neuroprotective effects in a large number of different experimental models (22)(23)(24)(25)(26)(27) and there is evidence suggesting that melatonin may affect glioblastoma growth. In a clinical trial in which melatonin was administered to patients being treated with radiation therapy for glioblastoma, a significant increase in one-year survival was seen (28).…”

“…High doses of valproic acid, a potent anti-epileptic, induce both upregulation of melatonin receptors and expression of neurotrophic factors in C6 glioma cells (25,29). It has been also reported that melatonin at millimolar concentrations reduces, both in vitro and in vivo, the growth of C6 glioma cells (26,30). This inhibition has been related to reduced intracellular peroxides and a subsequent inhibition of the activity of important intracellular effectors, such as Akt and nuclear factor (NF)-κB and protein kinase C (26,30).…”