Adenovirus-mediated transfer of caspase-8 augments cell death in gliomas: Implication for gene therapy

Caspase-8 is a member of the family of caspases, which are involved in the execution of apoptosis, To investigate whether caspase-8 can be used for ge ne therapy of gliomas, we transduced A-172 and U251 glioma cells with the c aspase-8 gene via an adenoviral vector (Adv) controlled by the chicken beta -actin (CA) promoter (Adv-caspase-8), and found that a similar level of cas pase-8 protein induced A-172 cells to undergo necrotic cell death and U251 cells to undergo apoptotic cell death. Neither Bcl-X-L nor Bcl-2, which pla y important roles in antiapoptotic mechanisms in gliomas, protected glioma cells from apoptosis induced by overexpression of caspase-8. Injection of A dv-caspase-8 suppressed the in vivo growth of U251 xenografts, in which apo ptotic cell death remarkably increased as revealed by TUNEL analysis. Final ly, we assessed whether gene therapy with a tissue-specific promoter, the m yelin basic protein (MBP) promoter, is applicable to gliomas. Adv for caspa se-8 controlled by the MBP promoter induced drastic apoptosis in U251 and U -373MG glioma cells, whereas it did not induce apoptosis in human endotheli al cells, fibroblasts, and nerve growth factor-treated PC12 cells. These re sults indicate that Adv for caspase-8 effectively induced cell death in gli omas, and that this approach may be a useful modality for gene therapy of g liomas.