Investigational new drugs, 2021-08, Vol.39 (4), p.949-960
2021
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- Autor(en) / Beteiligte
- Titel
- Autophagy promotes oncolysis of an adenovirus expressing apoptin in human bladder cancer models
- Ist Teil von
- Investigational new drugs, 2021-08, Vol.39 (4), p.949-960
- Ort / Verlag
- New York: Springer US
- Erscheinungsjahr
- 2021
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0167-6997eISSN: 1573-0646DOI: 10.1007/s10637-021-01073-xTitel-ID: cdi_proquest_miscellaneous_2486153348
- Format
- –
- Schlagworte
- 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