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

Aguirre-Hernández, Carmen; Maya-Pineda, Héctor Rubén; Millán, Julia San; Man, Yan-Gao; Lu, Yong‐Jie; Halldén, Gunnel

doi:10.1038/s41389-017-0020-8

Cited by 15 publications

(18 citation statements)

References 47 publications

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“…These mechanisms of resistance could be due to the acquisition of neuroendocrine features following lineage reprogramming, a well-described phenomenon linked with the acquisition of drug resistance in clinic [ 86 ]. This may also be due to autophagy upregulation, a phenomenon already observed in LNCaP cells after AA treatments including Enza and bicalutamide [ 87 ], and described as driving the resistance of PCa cells to bicalutamide, Enza, taxanes, mitoxanthrone and radiotherapy [ 88 ].…”

Section: Discussionmentioning

confidence: 99%

DNA Damage- But Not Enzalutamide-Induced Senescence in Prostate Cancer Promotes Senolytic Bcl-xL Inhibitor Sensitivity

Malaquin

Vancayseele

Gilbert

et al. 2020

Cells

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Cellular senescence is a natural tumor suppression mechanism defined by a stable proliferation arrest. In the context of cancer treatment, cancer cell therapy-induced senescence (TIS) is emerging as an omnipresent cell fate decision that can be pharmacologically targeted at the molecular level to enhance the beneficial aspects of senescence. In prostate cancer (PCa), TIS has been reported using multiple different model systems, and a more systematic analysis would be useful to identify relevant senescence manipulation molecular targets. Here we show that a spectrum of PCa senescence phenotypes can be induced by clinically relevant therapies. We found that DNA damage inducers like irradiation and poly (ADP-ribose) polymerase1 (PARP) inhibitors triggered a stable PCa-TIS independent of the p53 status. On the other hand, enzalutamide triggered a reversible senescence-like state that lacked evidence of cell death or DNA damage. Using a small senolytic drug panel, we found that senescence inducers dictated senolytic sensitivity. While Bcl-2 family anti-apoptotic inhibitor were lethal for PCa-TIS cells harboring evidence of DNA damage, they were ineffective against enzalutamide-TIS cells. Interestingly, piperlongumine, which was described as a senolytic, acted as a senomorphic to enhance enzalutamide-TIS proliferation arrest without promoting cell death. Overall, our results suggest that TIS phenotypic hallmarks need to be evaluated in a context-dependent manner because they can vary with senescence inducers, even within identical cancer cell populations. Defining this context-dependent spectrum of senescence phenotypes is key to determining subsequent molecular strategies that target senescent cancer cells.

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Section: Discussionmentioning

confidence: 99%

DNA Damage- But Not Enzalutamide-Induced Senescence in Prostate Cancer Promotes Senolytic Bcl-xL Inhibitor Sensitivity

Malaquin

Vancayseele

Gilbert

et al. 2020

Cells

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“…We previously generated an E1ACR2-deleted mutant that was designed to enhance potency in combination with apoptosis-inducing chemotherapeutic drugs by deleting the anti-apoptotic B-cell lymphoma-2 protein (Bcl-2) functional homologue E1B19K (Ad∆∆) [ 49 ]. In combination with cytotoxic drugs, Ad∆∆ showed superior efficacy compared to single drug regimens in preclinical models of drug-insensitive prostate and pancreatic cancers [ 50 , 51 ]. Synergistic tumour reduction was caused by improved viral infection followed by higher expression levels of the apoptosis-inducing and chemosensitising E1A-gene products that promote drug-induced DNA damage followed by aberrant mitosis and cell death [ 52 ].…”

Section: Replication-selective Adenovirusesmentioning

confidence: 99%

“…Intratumoural administration of the AdΔΔ oncolytic mutant caused synergistic cell killing and increased apoptotic death in combination with mitoxantrone or docetaxel in prostate cancer cells, and promoted tumour regression in murine PC3 and DU145 xenograft models [ 49 ]. The combination treatment of AdΔΔ and mitoxantrone was recently shown to promote increased apoptosis and attenuation of mitoxantrone-induced autophagy resulting in increased cell death in 22Rv1, PC3 and PC3-M prostate cancer cells [ 51 ].…”

Section: Replication-selective Adenovirusesmentioning

confidence: 99%

Designer Oncolytic Adenovirus: Coming of Age

Baker

Aguirre-Hernández

Halldén

et al. 2018

Cancers

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The licensing of talimogene laherparepvec (T-Vec) represented a landmark moment for oncolytic virotherapy, since it provided unequivocal evidence for the long-touted potential of genetically modified replicating viruses as anti-cancer agents. Whilst T-Vec is promising as a locally delivered virotherapy, especially in combination with immune-checkpoint inhibitors, the quest continues for a virus capable of specific tumour cell killing via systemic administration. One candidate is oncolytic adenovirus (Ad); it’s double stranded DNA genome is easily manipulated and a wide range of strategies and technologies have been employed to empower the vector with improved pharmacokinetics and tumour targeting ability. As well characterised clinical and experimental agents, we have detailed knowledge of adenoviruses’ mechanisms of pathogenicity, supported by detailed virological studies and in vivo interactions. In this review we highlight the strides made in the engineering of bespoke adenoviral vectors to specifically infect, replicate within, and destroy tumour cells. We discuss how mutations in genes regulating adenoviral replication after cell entry can be used to restrict replication to the tumour, and summarise how detailed knowledge of viral capsid interactions enable rational modification to eliminate native tropisms, and simultaneously promote active uptake by cancerous tissues. We argue that these designer-viruses, exploiting the viruses natural mechanisms and regulated at every level of replication, represent the ideal platforms for local overexpression of therapeutic transgenes such as immunomodulatory agents. Where T-Vec has paved the way, Ad-based vectors now follow. The era of designer oncolytic virotherapies looks decidedly as though it will soon become a reality.

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“…Two phase I trials are underway with VCN-01 in combination with gemcitabine We previously generated an E1ACR2-deleted mutant that was designed to enhance potency in combination with apoptosis-inducing chemotherapeutic drugs by deleting the anti-apoptotic Bcl-2 functional homologue E1B19K (Ad∆∆) 47 . In combination with cytotoxic drugs, Ad∆∆ had superior efficacy compared to single drug regimens in preclinical models of drug-insensitive prostate and pancreatic cancers 48,49 . Synergistic tumour reduction was caused by improved viral infection followed by higher expression levels of the apoptosis-inducing and chemosensitising E1A-gene products that promote drug-induced DNA damage followed by aberrant mitosis and cell death 50 .…”

Section: Replication-selective Adenovirusesmentioning

confidence: 99%

Designer Oncolytic Adenovirus: Coming of Age

Baker¹,

Aguirre-Hernández²,

Halldén³

et al. 2018

Preprint

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The licensing of Talimogene Laherparepvec (T-Vec) represented a landmark moment for oncolytic virotherapy, since it provided unequivocal evidence for the long-touted potential of genetically modified replicating viruses as anti-cancer agents. Whilst T-Vec is promising as a locally delivered virotherapy, especially in combination with Immune-checkpoint inhibitors, the quest continues for a virus capable of specific tumour cell killing via systemic administration. One candidate is oncolytic Adenovirus; it’s double stranded DNA genome is easily manipulated and a wide range of strategies and technologies have been employed to empower the vector with improved pharmacokinetics and tumour targeting ability. As well characterised clinical and experimental agents we have detailed knowledge of Adenoviruses mechanisms of pathogenicity, supported by detailed virological studies and in vivo interactions. In this review we highlight the strides made in the engineering of bespoke adenoviral vectors to specifically infect, replicate within, and destroy tumour cells. We discuss how mutations in genes regulating adenoviral replication after cell entry can be used to restrict replication to the tumour, and summarise how detailed knowledge of viral capsid interactions enable rational modification to eliminate native tropisms, and simultaneously promote active uptake by cancerous tissues. We argue that these designer-viruses, exploiting the viruses natural mechanisms and regulated at every level of replication, represent the ideal platforms for local overexpression of therapeutic transgenes such as immunomodulatory agents. Where T-Vec has paved the way, Ad based vectors now follow. The era of designer oncolytic virotherapies looks decidedly as though it will soon become a reality.

show abstract

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

Cited by 15 publications

References 47 publications

DNA Damage- But Not Enzalutamide-Induced Senescence in Prostate Cancer Promotes Senolytic Bcl-xL Inhibitor Sensitivity

DNA Damage- But Not Enzalutamide-Induced Senescence in Prostate Cancer Promotes Senolytic Bcl-xL Inhibitor Sensitivity

Designer Oncolytic Adenovirus: Coming of Age

Designer Oncolytic Adenovirus: Coming of Age

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