Genistein, a tyrosine kinase inhibitor, enhanced radiosensitivity in humanesophageal cancer cell lines in vitro: Possible involvement of inhibition of survival signal transduction pathways

Purpose: The effect of genistein, a tyrosine kinase inhibitor, on radiosens itivity was examined, especially focusing on "survival signal transduction pathways." Methods and Materials: Two human esophageal squamous cell cancer cell lines , TE-1 (p53, mutant) and TE-2 (p53, wild), were used. Radiosensitivity was determined by clonogenic assay, and activation of survival signals was exam ined by Western blot, Results: Genistein (30 muM) greatly enhanced radiosensitivity in these cell lines by suppressing radiation-induced activation of survival signals, p42 /p44 extracellular signal-regulated kinase and AKT/PKB, Significant increas e in the percentage of apoptotic cells and increased poly[ADP-ribose] polym erase cleavage were observed in TE-2, but not in TE-1 even after combinatio n of genistein with irradiation. In terms of changes in expression of p53-r elated proteins, increase in expression of Bax and decrease in that of Bcl- 2 were observed in TE-2 but not in TE-1, suggesting that the main mode of c ell death induced by genistein in a cell line with wild type p53 differed f rom that with mutant p53, Conclusions: This study suggested that survival signals, including p42/p44 ERK and AKT/PKB, may be involved in determining radiosensitivity, and genis tein would be a potent therapeutic agent that has an enhancing effect on ra diation, (C) 2001 Elsevier Science Inc.