Sensitisation to mitoxantrone-induced apoptosis by the oncolytic adenovirus Ad\u2206\u2206 through Bcl-2-dependent attenuation of autophagy

Carmen Aguirre-Hernández,Gunnel Halldén,Y K Stella Man,Julia San Millán,Héctor Maya-Pineda,Yong-Jie Lu

doi:10.1038/s41389-017-0020-8

Carmen Aguirre-Hernández, Gunnel Halldén + Show 4 more

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https://doi.org/10.1038/s41389-017-0020-8

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Journal: Oncogenesis	Publication Date: Jan 1, 2018
Citations: 12	License type: open-access

Affiliation: Queen Mary University of London

Abstract

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∆∆.

Highlights

Clinical safety and promising anti-tumour efficacy has been demonstrated for oncolytic adenoviral mutants targeting solid cancers, with significant tumour-regression in combination with cytotoxic drugs or radiation therapy, for example, the oncolytic mutants CG7870 and Ad5-yCD/ mutTK(SR39)rep-ADP1,2
The adenoviral mutants AdΔΔ and AdE1A12S synergistically enhance mitoxantrone-induced apoptosis in human prostate cancer cell lines We explored whether suboptimal doses (
The increased cell killing was synergistic with combination indexes (CI) < 0.9, which was significant with both mutants (p < 0.05) in PC3 and PC3M cells (Fig. 1b)

Summary

Introduction

Clinical safety and promising anti-tumour efficacy has been demonstrated for oncolytic adenoviral mutants targeting solid cancers, with significant tumour-regression in combination with cytotoxic drugs or radiation therapy, for example, the oncolytic mutants CG7870 and Ad5-yCD/ mutTK(SR39)rep-ADP1,2. Adenoviral mutants with deletions in the viral E1ACR2-region are the most promising clinical candidates with high potency and selectivity, such as dl[922-947] and AdΔ243–6. The E1ACR2 domain in the early viral E1A gene binds to pRb that inactivates the G1/S checkpoint and induces S-phase, which is essential for viral propagation in normal cells but not in cancer cells with deregulated cell cycle. E1B19K is a functional Bcl-2 homologue and plays a dual role in apoptosis and autophagy.

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