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Intracellular Signaling Pathways Involved in the Cell Growth
Inhibition of Glioma Cells by Melatonin
Vanesa Martín1, Federico
Herrera1, Pilar Carrera-Gonzalez1,2,
Guillermo García-Santos1,2, Isaac Antolín1,
Jezabel Rodriguez-Blanco1 and Carmen
Rodriguez1,2
1Departamento de Morfología y Biología
Celular and 2Instituto Universitario de Oncología del
Principado de Asturias, Facultad de Medicina de la Universidad de
Oviedo, Oviedo, Spain. Requests for reprints: Carmen Rodriguez,
Departamento de Morfología y Biología Celular, Facultad de Medicina
de la Universidad de Oviedo, Calle Julian Claveria, 33006 Oviedo,
Spain. Phone: 34-98-510-3057; Fax: 34-98-510-3618; E-mail: carro@uniovi.es.
Received 7/ 6/05; revised 9/28/05; accepted 10/20/05.
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 G1 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 κB
(NF-κB).
The antioxidant effect of melatonin in C6 cells is associated
to inhibition of NF-κB
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-κB.
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