title: Critical role of glutathione in melatonin enhancement of tumor necrosis factor and ionizing radiation-induced apoptosis in prostate cancer cells in vitro.
abstract: The role of antioxidants in reducing cancer initiation and progression has been highlighted in recent years. Not only antioxidants limit cancer cell growth but also, in some situations, they promote the effectiveness of conventional treatments. Melatonin, an endogenously synthesized antioxidant, reduces cell growth of several tumor types both in vivo and in vitro. Additionally, the indole limits the collateral damage induced by many chemotherapeutic agents. By using a cellular model of human prostate cancer, we studied the ability of melatonin to enhance apoptosis induced by tumor necrosis factor or gamma radiation. It has been reported that melatonin reduces prostate cancer cell growth and, more recently, it promotes cell differentiation. In this work, we also show that melatonin elevates p21 protein levels and increases antioxidant capacity of prostate cancer cells. In addition, melatonin significantly enhances hrTNFalpha induced cell death by decreasing NFkappaB activation. Bcl-2 and survivin down-regulation appears to be associated to apoptosis stimulation under NFkappaB inhibition. On the contrary, melatonin does not promote irradiation-induced cell death due to an increment in intracellular glutathione content. In conclusion, prevention of NFkappaB activation by melatonin enhances the effectiveness of cytokine treatment in prostate cancer cells but it is not sufficient to enhance cell death triggered by other therapies which generate free radicals. A crucial role of glutathione in survival mechanisms of prostate cancer cells should be carefully considered.
authors.affiliation: Departamento de Morfología y Biología Celular, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Spain. sainzrosa@uniovi.es
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Sainz
authors.forename: Russel J
authors.initials: RJ
authors.lastname: Reiter
authors.forename: Dun-Xian
authors.initials: DX
authors.lastname: Tan
authors.forename: Francis
authors.initials: F
authors.lastname: Roldan
authors.forename: Mohan
authors.initials: M
authors.lastname: Natarajan
authors.forename: Isabel
authors.initials: I
authors.lastname: Quiros
authors.forename: David
authors.initials: D
authors.lastname: Hevia
authors.forename: Carmen
authors.initials: C
authors.lastname: Rodriguez
authors.forename: Juan C
authors.initials: JC
authors.lastname: Mayo
mesh_terms: D000704:Analysis of Variance; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D019803:Glutathione Disulfide / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D008550:Melatonin / Q000378:metabolism* / Q000494:pharmacology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000503:physiopathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011839:Radiation, Ionizing; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D000077022:Survivin; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; C107489:BIRC5 protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D000077022:Survivin; D014409:Tumor Necrosis Factor-alpha; D005978:Glutathione; D008550:Melatonin; D019803:Glutathione Disulfide