13 research outputs found
What does patient engagement mean for Canadian National Transplant Research Program Researchers?
PML involvement in the p73-mediated E1A-induced suppression of EGFR and induction of apoptosis in head and neck cancers
Evaluation of apoptogenic adenovirus type 5 oncolytic vectors in a Syrian hamster head and neck cancer model
Mapping of IgE and IgG<sub>4</sub> Antibody-Binding Epitopes in Cyn d 1, the Major Allergen of Bermuda Grass Pollen
Sensitisation to mitoxantrone-induced apoptosis by the oncolytic adenovirus Ad Delta Delta through Bcl-2-dependent attenuation of autophagy
Anti-apoptotic Bcl-2 is frequently activated in human malignant cells to promote cell survival and inhibit cell death. Replication-selective oncolytic adenoviruses deleted in the functional Bcl-2 homologue E1B19K potently synergise with apoptosis-inducing chemotherapeutic drugs, including mitoxantrone for prostate cancer. Here, we demonstrate that our previously generated oncolytic mutant Ad∆∆ (E1B19K- and E1ACR2-deleted) caused potent synergistic apoptotic cell death in both drug-sensitive 22Rv1, and drug-insensitive PC3 and PC3M prostate cancer cells. The synergistic cell killing was dependent on Bcl-2 expression and was prevented by Bcl-2 knockdown, which led to activation of the autophagy pathway. Mitoxantrone-induced autophagy, which was decreased in combination with Ad∆∆-infection resulting in increased apoptosis. Expression of the viral E1A12S protein alone mimicked the synergistic effects with Ad∆∆ in combination with mitoxantrone while intact wild-type virus (Ad5) had no effect. Early and late-stage inhibition of autophagy by Atg7 knockdown and chloroquine respectively, promoted apoptotic cell killing with mitoxantrone similar to Ad∆∆. These findings revealed currently unexplored actions of E1B19K-deleted oncolytic adenoviruses and the central role of Bcl-2 in the synergistic cell killing. This study suggests that cancers with functional Bcl-2 expression may be selectively re-sensitised to drugs by Ad∆∆