Abstract：
:A prominent feature of glioblastoma is its resistance to death from Fas pathway activation. In this study, we explored the modulation of Fas-induced glioblastoma death with chemotherapeutic agents. Camptothecin significantly increased the glioblastoma cell death response to Fas receptor activation regardless of p53 status. Sublethal concentrations of camptothecin reduced the IC50 of agonistic anti-Fas antibody (CH-11) 10-fold, from 500 to 50 ng/mL, in human U87 glioblastoma cells (p53 wild-type). Cell viability in response to camptothecin, CH-11 alone, and the combination of camptothecin + CH-11 was found to be 84%, 85%, and 47% (P < 0.001), respectively. A similar pattern of relative cytotoxicity was found in U373 cells (p53 mutant). We further examined the pathways and mechanisms involved in this apparent synergistic cytotoxic response. Cell death was found to be predominantly apoptotic involving both extrinsic and intrinsic pathways as evidenced by annexin V staining, cleavage of caspases (3, 8, and 9), increased caspase activities, Smac release, and cytoprotection by caspase inhibitors. Expression of Fas-associated death domain, and not Fas, Fas ligand, or caspase proteins, increased following cell treatment with camptothecin + CH-11. Camptothecin treatment enhanced c-jun-NH2-kinase activation in response to CH-11, but inhibition of c-jun-NH2-kinase did not prevent cell death induced by the combination treatment. Reactive oxygen species, especially H2O2, were elevated following camptothecin treatment; and H2O2 enhanced cell death induced by CH-11. The antioxidants glutathione and N-acetyl-cysteine prevented cell death induced by camptothecin + CH-11. These findings show that camptothecin synergizes with Fas activation to induce glioblastoma apoptosis via a mechanism involving reactive oxygen species and oxidative stress pathways.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Xia S,Rosen EM,Laterra Jdoi
10.1158/0008-5472.CAN-04-4332subject
Has Abstractpub_date
2005-06-15 00:00:00pages
5248-55issue
12eissn
0008-5472issn
1538-7445pii
65/12/5248journal_volume
65pub_type
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