Synergistic efficacy of telomerase-specific oncolytic adenoviral therapy and histone deacetylase inhibition in human hepatocellular carcinoma

Zhong-Zhe Lin; Mickey C-T Hu; Chiun Hsu; Yao-Ming Wu; Yen-Shen Lu; Ja-An Annie Ho; Shiou-Hwei Yeh; Pei-Jer Chen; Ann-Lii Cheng

doi:10.1016/j.canlet.2023.216063

Synergistic efficacy of telomerase-specific oncolytic adenoviral therapy and histone deacetylase inhibition in human hepatocellular carcinoma

Cancer Lett. 2023 Mar 1:556:216063. doi: 10.1016/j.canlet.2023.216063. Epub 2023 Jan 18.

Authors

Zhong-Zhe Lin¹, Mickey C-T Hu², Chiun Hsu³, Yao-Ming Wu⁴, Yen-Shen Lu⁵, Ja-An Annie Ho⁶, Shiou-Hwei Yeh⁷, Pei-Jer Chen⁸, Ann-Lii Cheng⁹

Affiliations

¹ Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan; Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
² Panorama Research Institute, Sunnyvale, CA, USA.
³ Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan; Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan.
⁴ Department of Surgery, College of Medicine, National Taiwan University, Taipei, Taiwan.
⁵ Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
⁶ Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan.
⁷ Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
⁸ Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
⁹ Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan; Departments of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: alcheng@ntu.edu.tw.

PMID: 36669725
DOI: 10.1016/j.canlet.2023.216063

Abstract

The telomerase-specific oncolytic adenovirus Telomelysin and the histone deacetylase inhibitor AR42 have demonstrated anticancer effects in preclinical models of human hepatocellular carcinoma (HCC). However, the clinical development of Telomelysin may be hindered by human antiviral immunity and tumor resistance. Combining oncolytic and epigenetic therapies is a viable approach for treating various cancers. This study investigated the potential synergism of Telomelysin and AR42 and the relevant underlying mechanisms. Telomelysin and AR42 exhibited synergistic antiproliferative effects in human HCC models in vitro and in vivo. Apoptosis induced by Telomelysin was significantly enhanced by AR42 in both PLC5 and Hep3B HCC cells. AR42 treatment unexpectedly attenuated the expression of the coxsackievirus and adenovirus receptor and the mRNA levels of human telomerase reverse transcriptase, which may be positively associated with the cytotoxicity of Telomelysin. Meanwhile, the cellular antiviral interferon response was not altered by AR42 treatment. Further, we found that Telomelysin enhanced Akt phosphorylation in HCC cells. AR42 reduced Telomelysin-induced phospho-Akt activation and enhanced Telomelysin-induced apoptosis. The correlation of Akt phosphorylation with drug-induced apoptosis was validated in HCC cells with upregulated or downregulated Akt signaling. Combination therapy with Telomelysin and AR42 demonstrated synergistic anti-HCC efficacy. Clinical trials investigating this new combination regimen are warranted.

Keywords: Akt; HDAC inhibitor; Hepatocellular carcinoma; Oncolytic adenovirus; Telomelysin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenoviridae / genetics
Apoptosis
Carcinoma, Hepatocellular* / therapy
Cell Line, Tumor
Histone Deacetylases / metabolism
Humans
Liver Neoplasms* / genetics
Liver Neoplasms* / therapy
Oncolytic Virotherapy*
Proto-Oncogene Proteins c-akt / metabolism
Telomerase* / genetics
Telomerase* / metabolism

Substances

Telomerase
Proto-Oncogene Proteins c-akt
Histone Deacetylases