Abstract A69: High‐throughput library screening identifies phytochemical inducers of phase II metabolism enzymes GSTP1 and NQO1 in human lung cells

Many phytochemicals possess cancer‐preventive properties, some putatively through phase II metabolism‐mediated mutagen/oxidant quenching. However, in studies to date, most candidate agents are not active in human lung cells. In vitro and in vivo screening studies for discovery are clearly needed for new, more potent chemopreventive agents for lung cancer. Here we applied a gene expression‐based high‐throughput screening approach to identify phytochemical inducers of phase II metabolism enzymes GSTP1 and NQO1 in primary normal human bronchial epithelial (NHBE) cells and immortalized human bronchial epithelial cells (HBEC). We have screened 800 compounds in the MicroSource Natural Products Library for inducers of GSTP1 and NQO1 expression, and identified 2, 3‐dihydroxy‐4‐methoxy‐4′‐ethoxybenzophenone, triacetylresveratrol, ivermectin, sanguinarine sulfate, and daunorubicin as new inducers for GSTP1 and NQO1 mRNA expression. Consistent with this effect, the induction of NQO1 protein expression by immunoblot was found for all these agents in both HBEC and NHBE cells at the same concentration (1.0 µM, final concentration) that induced NQO1 mRNA expression. However, GSTP1 protein expression did not significantly change with any selected agents. Proliferation/viability assays showed that HBEC and NHBE were significantly inhibited by ivermectin, sanguinarine sulfate, and daunorubicin. These data demonstrate the feasibility of high‐throughput screening for inducers of NQO1. Moreover, the data identify 2, 3‐dihydroxy‐4‐methoxy‐4′‐ethoxybenzophenone and triacetylresveratrol as most potent and low toxicity inducers [12‐fold, and 10‐fold, respectively, at the protein level], implying they are potential new agents for further in vitro and preclinical in vivo testing for prevention of tobacco‐related lung cancer. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A69.