Original Article

Cancer Gene Therapy (2003) 10, 803–813. doi:10.1038/sj.cgt.7700644

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

Yuji Saito1, Began Gopalan1, Abner M Mhashilkar2, Jack A Roth1, Sunil Chada2, Louis Zumstein2 and Rajagopal Ramesh1

  1. 1Department of Thoracic and Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
  2. 2Introgen Therapeutics, Inc., Houston, Texas, USA

Correspondence: Dr. Rajagopal Ramesh, PhD, Department of Thoracic and Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 445, Houston, TX 77030, USA. E-mail: rramesh@mdanderson.org

Received 3 April 2003.

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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.

Keywords:

PTEN, caffeine, colorectal cancer, apoptosis, synergy, gene therapy