Adenovirus-mediated PTEN treatment combined with caffeine produces a synergistic therapeutic effect in colorectal cancer cells.
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 G(2)/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.
Saito
Yuji
Y
Department of Thoracic and Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Gopalan
Began
B
Mhashilkar
Abner M
AM
Roth
Jack A
JA
Chada
Sunil
S
Zumstein
Louis
L
Ramesh
Rajagopal
R
D000256:Adenoviridae / Q000235:genetics*; D017209:Apoptosis / Q000187:drug effects; D002110:Caffeine / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003106:Colon / Q000166:cytology / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*; D004357:Drug Synergism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008938:Mitosis / Q000187:drug effects / Q000235:genetics; D051059:PTEN Phosphohydrolase; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000235:genetics* / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011839:Radiation, Ionizing; D012016:Reference Values; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D011518:Proto-Oncogene Proteins; D002110:Caffeine; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017027:Protein Tyrosine Phosphatases; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat