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Adenovirus-mediated PTEN treatment combined with caffeine produces a synergistic therapeutic effect in colorectal cancer cells

Cancer Gene Therapy volume 10, pages 803–813 (2003)Cite this article

Abstract

The tumor suppressor phosphatase and tensin homologue deleted from chromosome 10 (PTEN) gene is a negative regulator of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt/PKB) signaling pathway. Overexpression of PTEN in cancer cells results in cell-cycle arrest and cell death through inhibition of PI3K. Caffeine, a xanthine analogue, is well known to enhance the cytocidal and growth-inhibitory effects of DNA-damaging agents such as radiation, UV light, and anticancer agents on tumor cells by abrogating DNA-damage checkpoints through inhibition of ataxia-telangiectasia-mutated (ATM), and ATM and Rad3-related (ATR) kinase activity. In this study, we demonstrate that treatment with a combination of adenovirus-mediated transfer of PTEN (Ad-PTEN) and caffeine synergistically suppressed cell growth and induced apoptosis in colorectal cancer cells but not in normal colorectal fibroblast cells. This synergistic effect was induced through abrogation of G2/M arrest, downregulation of the Akt pathway, and modulation of the p44/42MAPK pathway. Thus, combined treatment with Ad-PTEN and caffeine is a potential therapy for colorectal cancer.

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Acknowledgements

We thank Kathryn Hale for editorial assistance and Alma Vega for help in the preparation of this manuscript. This study was partially supported by the Texas Higher Education Coordinating Board ATP/ARP Grant 003657-0078-2001 (RR), by Public Health Service Grant PO1-CA 78778-01A1 (JAR), by a Career Development award from The University of Texas SPORE in Lung Cancer P50CA70907-5 (RR), by M.D. Anderson Cancer Center Institutional Research Grant (RR), by M.D. Anderson Cancer Center Support Grant CA16672, by the W.M. Keck Foundation Fund for Human Cancer Gene Prevention and Therapy (RR), by a BESCT Lung Cancer Program Grant (DAMD17-01-1-0689), by a TARGET Lung Cancer Grant (DAMD17-02-1-0706), and by a sponsored research agreement with Introgen Therapeutics, Inc.

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Authors and Affiliations

  1. Department of Thoracic and Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

    Yuji Saito, Began Gopalan, Jack A Roth & Rajagopal Ramesh

  2. Introgen Therapeutics, Inc., Houston, Texas, USA

    Abner M Mhashilkar, Sunil Chada & Louis Zumstein

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  1. Yuji Saito
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Correspondence to Rajagopal Ramesh.

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Saito, Y., Gopalan, B., Mhashilkar, A. et al. Adenovirus-mediated PTEN treatment combined with caffeine produces a synergistic therapeutic effect in colorectal cancer cells. Cancer Gene Ther 10, 803–813 (2003). https://doi.org/10.1038/sj.cgt.7700644

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