Molecular targets for chemoprevention

Muneyuki Masuda, Masumi Suzui, Jin Lim, I. Bernard Weinstein, Herbert Irving

Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, New York, NY10032

Recent studies on pathways of signal transduction and cell cycle control suggest novel molecular target for both cancer chemoprevention and treatment. In this study we focused on EGFR-mediated pathways, and utilized the green tea compound EGCG because of its known chemopreventive activity. We used head and neck squamous cell carcinoma (HNSCC) cells because autocrine activation of TGF-a/EGFR frequently correlates with the development and progression of this malignancy. Treatment with EGCG arrested cells in G1 and induced apoptosis. In the treated cells there was a decrease in cyclin D1, an increase in p21Cip1 and p27Kip1 and a reduction in hyperphosphorylated pRb, changes which explain the arrest in G1. EGCG also caused a decrease in Bcl-2 and Bcl-XL, an increase in Bax, and activation of caspase 9, suggesting that EGCG induces apoptosis via a mitochondrial pathway. EGCG inhibited phosphorylation of the EGFR, Stat3 and ERK proteins, inhibited basal and TGF-a-stimulated c-fos and cyclin D1 prompter activity, and inhibited VEGF promoter activity and VEGF production. At 0.1 mg/ml (a concentration found in serum after oral administration) EGCG markedly enhanced the growth inhibitory effects of 5-FU. Therefore, EGCG targets pathways involved in cell cycle progression, mitogenic signaling, apoptosis and angiogenesis. The relevance of these findings to the use of this natural compaund, alone or in combination with other agents, in cancer chemoprevention and therapy will be discussed.

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Molecular Genetics & Therapy - 1.