Invest New Drugs.2021 Aug;39(4):949-960.doi: 10.1007/s10637-021-01073-x.Epub 2021 Feb 3.

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

Chao Shang  1 Yi-Long Zhu  2 Yi-Quan Li  2 Gao-Jie Song  3 Chen-Chen Ge  3 Jing Lu  3 Zhi-Ru Xiu  2 Wen-Jie Li  1 Shan-Zhi Li  2 Jia-Nan Cong  1 Zi-Rui Liu  1 Xiao Li  4   5   6   7 Li-Li Sun  8   9 Ning-Yi Jin  10   11   12   13 Affiliations

Abstract

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.

Keywords: AMPK; Adenovirus; Autophagy; Bladder cancer; Rapamycin.

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