Ebselen sensitizes glioblastoma cells to Tumor Necrosis Factor (TNFalpha)-induced apoptosis through two distinct pathways involving NF-kappaB downregulation and Fas-mediated formation of death inducing signaling complex.
Resistance to tumor necrosis factor (TNFalpha)-induced apoptosis in various cancer cells has been attributed to the activation of the transcription factor NF-kappaB. Ebselen (2-phenyl-1,2-benzisoselenazol-3[2H]one)-a selenoorganic compound is known to prevent TNFalpha-mediated NF-kappaB activity. As glioblastoma are resistant to the cytotoxic effect of TNFalpha, we investigated the potential of Ebselen in sensitizing glioma cells to TNFalpha-induced apoptosis. Although treatment with Ebselen reduced viability of glioma cells, cotreatment with TNFalpha enhanced apoptosis further through alteration of TNFalpha-mediated signaling pathways. Sensitization of TNFalpha activated glioma cells to apoptosis by Ebselen involved 2 pathways: (i) abrogation of TNFalpha induced NF-kappaB activation and (ii) induction of Fas-associated death inducing signaling complex (DISC) formation. Ebselen inhibited the prosurvival pathway mediated by NF-kappaB by altering the association of TNF receptor associated factor 2 (TRAF2) with TNFalpha receptor associated death domain (TRADD) in the TNFR1-TRADD-TRAF2 complex -an interaction crucial for mediating NF-kappaB activity. Ebselen also induced the formation of DISC involving Fas, Fas-associated death domain (FADD) and active caspase 8 to transduce apoptotic signals in situations where NF-kappaB function was inhibited. Cotreatment with Ebselen and TNFalpha induced G2/M phase arrest in cell cycle and modulated the expression of molecules involved in cell cycle progression. These results raise the possibility of overcoming resistance to TNFalpha-induced apoptosis by cotreatment with organoselenium Ebselen as a strategy to kill glioma cells.
Sharma
Vivek
V
National Brain Research Centre, Manesar, Haryana, India.
Tewari
Richa
R
Sk
Ugir Hossain
UH
Joseph
Christy
C
Sen
Ellora
E
D017209:Apoptosis / Q000187:drug effects*; D001393:Azoles / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D054833:Isoindoles; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics; D016566:Organoselenium Compounds / Q000494:pharmacology*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D015398:Signal Transduction; D053199:TNF Receptor-Associated Death Domain Protein / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019014:fas Receptor / Q000502:physiology*
D001393:Azoles; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D054833:Isoindoles; D016328:NF-kappa B; D016566:Organoselenium Compounds; D047888:Receptors, Tumor Necrosis Factor, Type I; D053199:TNF Receptor-Associated Death Domain Protein; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C042986:ebselen