Anti-tumor effects by a synthetic chalcone compound is mediated by c-Myc-mediated reactive oxygen species production

Abstract

Overexpression of c-Myc represents the most frequently deregulated genetic event in cancer, and therefore c-Myc may represent a good molecular target for cancer therapy. The human lung carcinoma cell line, NCl-H1299, shows resistance to conventional cancer treatments, such as ionizing radiation (IR) and cisplatin, while the lung carcinoma cell line, NCl-H460, is sensitive to treatment with these agents. However, when treated with a chalcone compound [toluenesulfonylamido-chalcone, 4'-(p-toluene sulfonyl amino)-3,4-dihydroxy chalcone (TSHDC)], cell death was dramatically induced in NCl-H1299 cells as compared to NCl-H460 cells. TSHDC-mediated cytotoxicity was not dependent on the status of p53 and p21. However, TSHDC exerted increased c-Myc-dependent reactive oxygen species (ROS) production in NCl-H1299 cells in which c-Myc is overexpressed, while increased ROS production did not occur in A549 or NCl-H460 cells with a low c-Myc level. Several colon and brain cancer cells also showed a correlation between c-Myc expression and TSHDC-mediated increased cell death. Tumor regression by TSHDC was more dramatic in NCl-H1299 cells than NCl-H460 cells, when these cells were grafted to nude mice. However, in the case of IR and cisplatin. NCl-H460 cells were more sensitive than NCl-H1299 cells. From these results, c-Myc-mediated ROS production may be a good target for screening of novel cancer drugs and TSHDC might be a good candidate as a cancer drug, specifically in cancer cells that overexpress c-Myc. (C) 2010 Elsevier Ireland Ltd. All rights reserved.