Autophagy promotes oncolysis of an adenovirus expressing apoptin in human bladder cancer models

Summary As a potential cancer therapy, we developed a recombinant adenovirus named Ad-VT, which was designed to express the apoptosis-inducing gene (apoptin) and selectively replicate in cancer cells via E1a manipulation. However, how it performs in bladder cancer remains unclear. We examined the an...

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Bibliographic Details
Published in:Investigational new drugs 2021-08, Vol.39 (4), p.949-960
Main Authors: Shang, Chao, Zhu, Yi-Long, Li, Yi-Quan, Song, Gao-Jie, Ge, Chen-Chen, Lu, Jing, Xiu, Zhi-Ru, Li, Wen-Jie, Li, Shan-Zhi, Cong, Jia-Nan, Liu, Zi-Rui, Li, Xiao, Sun, Li-Li, Jin, Ning-Yi
Format: Article
Language:English
Subjects:
Adenoviridae - genetics
Adenoviruses
AMP-Activated Protein Kinases - metabolism
Animal models
Animals
Anticancer properties
Antitumor activity
Apoptosis
Autophagy
Autophagy - genetics
Birds of prey
Bladder
Bladder cancer
Cancer
Capsid Proteins - genetics
Cell culture
Cell death
Cell Line, Tumor
Cholecystokinin
Female
HEK293 Cells
Humans
Medicine
Medicine & Public Health
Mice
Mice, Inbred BALB C
Mice, Nude
Oncology
Oncolysis
Oncolytic Virotherapy - methods
Phagocytosis
Pharmacology/Toxicology
Preclinical Studies
Rapamycin
Regulatory-Associated Protein of mTOR - metabolism
Signal transduction
Signal Transduction - drug effects
Survival
TOR protein
TOR Serine-Threonine Kinases - metabolism
Tumors
Urinary Bladder Neoplasms - genetics
Urinary Bladder Neoplasms - therapy
Western blotting
Xenograft Model Antitumor Assays
Xenografts
Xenotransplantation
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Summary:Summary As a potential cancer therapy, we developed a recombinant adenovirus named Ad-VT, which was designed to express the apoptosis-inducing gene (apoptin) and selectively replicate in cancer cells via E1a manipulation. However, how it performs in bladder cancer remains unclear. We examined the antitumor efficacy of Ad-VT in bladder cancers using CCK-8 assays and xenograft models. Autophagy levels were evaluated by western blotting, MDC staining, and RFP-GFP-LC3 aggregates’ analyses. Here, we report the selective replication and antitumor efficacy (viability inhibition and apoptosis induction) of Ad-VT in bladder cancer cells. Using xenograft tumor models, we demonstrate that its effects are tumor specific resulting in the inhibition of tumor growth and improvement of the survival of mice models. Most Importantly, Ad-VT induced a complete autophagy flux leading to autophagic cancer cell death through a signaling pathway involving AMPK, raptor and mTOR. Finally, we suggest that treatment combination of Ad-VT and rapamycin results in a synergistic improvement of tumor control and survival compared to monotherapy. This study suggests that Ad-VT can induce selective autophagic antitumor activities in bladder cancer through the AMPK-Raptor-mTOR pathway, which can be further improved by rapamycin.
ISSN:0167-6997
1573-0646
DOI:10.1007/s10637-021-01073-x