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ADP-overexpressing adenovirus elicits enhanced cytopathic effect by induction of apoptosis

Cancer Gene Therapy volume 12, pages 61–71 (2005)Cite this article

Abstract

Replication-competent adenoviruses (Ad's) are emerging as a promising new modality for treatment of cancer. Selective replication of viral agents in tumor may lead to improved efficacy over nonreplicating Ad's due to their inherent ability to multiply, lyse, and spread to surrounding cells. We have previously shown that an E1B 55 kDa-deleted adenovirus (YKL-1) exhibits tumor-specific replication and cell lysis, but its cytolytic effects were reduced in comparison to the wild-type adenovirus. To increase the oncolytic potency of YKL-1, we have reintroduced the Ad death protein (ADP) gene under the control of either a CMV or an MLP promoter at the E3 region of YKL-1, generating YKL-cADP and YKL-mADP Ad's, respectively. ADP is an 11.6 kDa protein encoded by the E3 transcription unit, and is required to kill adenovirus-infected cells efficiently. However, to date, the mechanism by which ADP mediates cell death has not been clearly defined. In this study, we report that ADP-overexpressing Ad markedly enhanced cytolytic effect (up to 100-fold) against all tumor cell lines tested, but did not increase cytopathic effect in normal skin fibroblast, BJ. Moreover, plaque size formed by YKL-cADP was substantially larger than that of YKL-1, indicating an enhancement in cell lysis. TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) assay and Annexin-V/PI double staining indicate that ADP-mediated cytotoxicity was largely driven by apoptosis. Finally, YKL-cADP adenovirus also showed superior antitumor effect than YKL-1 and YKL-mADP in C33A cervical and Hep3B hepatoma xenograft tumor models. Taken together, these lines of evidence demonstrate that the newly generated adenovirus expressing ADP under the CMV promoter induces efficient but tumor-selective cell lysis, which is critical for adding therapeutic value to replicating adenovirus for its use in cancer gene therapy.

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Acknowledgements

We thank all of our colleagues at Yonsei Cancer Center, Seoul, Korea, who have contributed to these studies. This work was supported by grants from the Ministry of Commerce Industry and Energy, Republic of Korea (990-14-05-00008131, Dr. C-O Yun) and the Korea Food and Drug Administration, Republic of Korea (KFDA-03132-GEN-080-5, Dr. C-O Yun). Eunhee Kim, Young-sook Lee, and Taeyoung Koo are graduate students sponsored by the Brain Korea 21 Project for Medical Science, Yonsei University, Seoul, South Korea.

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  1. Chae-Ok Yun and Eunhee Kim: These authors contributed equally to the work.

Authors and Affiliations

  1. Brain Korea 21 Project for Medical Sciences, Institute for Cancer Research, Yonsei Cancer Center,

    Chae-Ok Yun, Eunhee Kim, Taeyoung Koo, Young-sook Lee & Joo-Hang Kim

  2. Department of Pathology, Yonsei University College of Medicine, Seoul, Korea

    Hoguen Kim

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Correspondence to Chae-Ok Yun.

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Yun, CO., Kim, E., Koo, T. et al. ADP-overexpressing adenovirus elicits enhanced cytopathic effect by induction of apoptosis. Cancer Gene Ther 12, 61–71 (2005). https://doi.org/10.1038/sj.cgt.7700769

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