Antitumor B (ATB), also known as Zeng Sheng Ping, is a Chinese herbal mixture composed of six plants including Sophora tonkinensis, Polygonum bistorta, Prunella vulgaris, Sonchus brachyotus, Dictambus dasycarpus, and Dioscorea bulbifera. Previously, clinical studies have shown a significant chemopreventive efficacy of ATB against human esophageal and lung cancers. Our preliminary data indicate that ATB act as an effective chemopreventive agent of lung cancer in benzo(a)pyrene-induced lung carcinogenesis in A/J mice harboring a dominant-negative p53 and/or heterozygous deletion of Ink4a/Arf. While mice with all genotypes treated with ATB displayed a significant reduction in lung cancer multiplicity and tumor load, ATB exhibited an enhanced inhibitory effect in animals harboring all three genetic alterations (Kras2, p53, and Ink4A). We hypothesized that ATB will prevent chemically induced lung adenocarcinoma in a mutant mouse model with genetic changes commonly seen in human lung cancers, and the chemopreventive effect of ATB and its active components is, in part, mediated by inhibition of cell proliferation via inhibition of AP-1. Accordingly, we propose the following specific aims: 1) Identification of key active components of ATB via fractionation and in vitro screening assays; 2) Determination of the efficacy of selected key active components using in vivo mouse models of lung cancer; 3) Pharmacokinetic and biopharmaceutical characterization of ATB and its active components; and 4) Investigation of mechanisms of action of anti-tumor B and key active components in chemoprevention against the lung cancers. This proposal is timely and significant for the following reasons. Firstly, the ongoing chemoprevention clinical trial of ATB against lung cancer in humans requires rigorous preclinical characterization of its efficacy and mechanism(s). Secondly, we will use a newly developed mouse models of lung adenocarcinomas that share both histopathological features and genetic alterations (activated oncogenes and inactivated tumor suppressors) observed in human lung cancer. And thirdly, we will conduct comprehensive chemical fractionation and pharmacokinetic characterizations of ATB's active components. The results from this proposal will provide a solid foundation for clinical trials of ATB as a lung cancer chemopreventive agent. Furthermore, the results from this proposal will also provide significant insights on the active inhibitory components and how they affect lung carcinogenesis process. ? ? ?
