Death receptor-independent cytochrome c release and caspase activation mediate thymidine kinase plus ganciclovir-mediated cytotoxicity in LN-18 and LN-229 human malignant glioma cells

Gene Therapy
T GlaserMichael Weller

Abstract

Suicide gene therapy using viral transfer of herpes simplex virus type I (HSV-1) thymidine kinase (TK) and subsequent ganciclovir (GCV) chemotherapy was the first approach used in clinical trials of somatic gene therapy for glioblastoma. The molecular pathways mediating TK/GCV-induced cell death remain to be elucidated. Here, we report that adenoviral (Ad)-TK/GCV-induced death is p53-independent and does not involve altered CD95 or CD95L expression. Ectopic expression of the preferential caspase 8 inhibitor, crm-A, inhibits Ad-CD95L-induced cell death but has no effect on TK/GCV cytotoxicity. LN-18 glioma cells selected for resistance to death receptor-mediated cell death do not acquire cross-resistance to TK/GCV. TK/GCV triggers mitochondrial cytochrome c release and activation of caspases 3, 7, 8 and 9 in a death receptor-independent manner. These events are associated with the loss of BCL-X(L). Forced expression of a BCL-X(L) transgene, or co-exposure to a pseudosubstrate caspase inhibitor, zVAD-fmk, inhibit TK/GCV cytotoxicity. Double-transfected cell lines expressing crm-A and enhanced green fluorescent protein (eGFP) show that the bystander effect in vitro is also death receptor- and caspase 8-independent. TK/GCV therapy ...Continue Reading

References

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Citations

Jun 27, 2006·Molecular Therapy : the Journal of the American Society of Gene Therapy·Marianela CandolfiMaria G Castro
Jan 27, 2005·Biochemical and Biophysical Research Communications·Martin UhlUlrich Herrlinger
Jul 6, 2010·Biochimica Et Biophysica Acta·Daniel Abate-DagaCristina Fillat
Jun 28, 2005·Journal of Neuro-oncology·Chitra SarkarSubrata Sinha
Jun 3, 2021·Nanomaterials·Vicente Candela-NogueraRamón Martínez-Máñez

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