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p73β-expressing recombinant adenovirus: a potential anticancer agent

Cancer Gene Therapy volume 12, pages 417–426 (2005)Cite this article

Abstract

Tumor suppressor p53-based gene therapy strategy is ineffective in certain conditions. p73, a p53 homologue, could be a potential alternative gene therapy agent as it has been found to be an important determinant of chemosensitivity in cancer cells. Previously, we have reported the generation of a replication-deficient adenovirus expressing p73β (Ad-p73). In this study, we evaluated the therapeutic potential of Ad-p73 against a panel of cancer cells (n=12) of different tissue origin. Ad-p73 infected all the cell lines tested very efficiently resulting in several-fold increase in p73β levels, which is also functional as it activated the known target gene p21WAF1/CIP1. Infection with Ad-p73 resulted in potent cytotoxicity in all the cell lines tested. The mechanism of p73-induced cytotoxicity in these cell lines is found to be due to a combination of cell cycle arrest and induction of apoptosis. In addition, exogenous overexpression of p73 by Ad-p73 infection increased the chemosensitivity of cancer cells by many fold to commonly used drug adriamycin. Moreover, Ad-p73 is more efficient than Ad-p53 in enhancing the chemosensitivity of mutant p53 harboring cells. Furthermore, Ad-p73 infection did not induce apoptosis in human normal lung fibroblasts (HEL 299) and human immortalized keratinocytes (HaCaT). These results suggest that Ad-p73 is a potent cytotoxic agent specifically against cancer cells and could be developed as a cancer gene therapy agent either alone or in combination with chemotherapeutic agents.

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Abbreviations

wt:

wild-type

mut:

mutant

BrdU:

bromodeoxyuridine

MOI:

multiplicity of infection

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Acknowledgements

We thank Dr Omana Joy for technical assistance in FACS experiments. This study was supported partly by grants from Life Science Research Board, DRDO, and Council of Scientific and Industrial Research (CSIR), Government of India. Funding from ICMR (Center for Advanced studies in Molecular Medicine), DBT (Program support), DST (FIST) and UGC (Special assistance) to Department of Microbiology and Cell Biology is also acknowledged. KS is a Wellcome Trust International Senior Research Fellow. SD, SN, and SA are supported by fellowships from CSIR, Government of India.

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Authors and Affiliations

  1. Department of Microbiology and Cell Biology, Indian Institute of Science, Sir CV Raman Road, Bangalore, 560012, India

    Sanjeev Das, Srikanth Nama, Sini Antony & Kumaravel Somasundaram

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  1. Sanjeev Das
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  2. Srikanth Nama
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Correspondence to Kumaravel Somasundaram.

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Das, S., Nama, S., Antony, S. et al. p73β-expressing recombinant adenovirus: a potential anticancer agent. Cancer Gene Ther 12, 417–426 (2005). https://doi.org/10.1038/sj.cgt.7700803

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