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.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Research Project (R01)
Project #
5R01AT003203-03
Application #
7678414
Study Section
Special Emphasis Panel (ZRG1-ONC-B (02))
Program Officer
Hopp, Craig
Project Start
2007-09-30
Project End
2010-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
3
Fiscal Year
2009
Total Cost
$368,725
Indirect Cost
Name
Washington University
Department
Surgery
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Yin, Taijun; Yang, Guanyi; Ma, Yong et al. (2015) Developing an activity and absorption-based quality control platform for Chinese traditional medicine: Application to Zeng-Sheng-Ping(Antitumor B). J Ethnopharmacol 172:195-201
Leikauf, George D; Concel, Vincent J; Bein, Kiflai et al. (2013) Functional genomic assessment of phosgene-induced acute lung injury in mice. Am J Respir Cell Mol Biol 49:368-83
Xiong, Donghai; Li, Guangming; Li, Kezhen et al. (2012) Exome sequencing identifies MXRA5 as a novel cancer gene frequently mutated in non-small cell lung carcinoma from Chinese patients. Carcinogenesis 33:1797-805
Leikauf, George D; Pope-Varsalona, Hannah; Concel, Vincent J et al. (2012) Integrative assessment of chlorine-induced acute lung injury in mice. Am J Respir Cell Mol Biol 47:234-44
Leikauf, George D; Concel, Vincent J; Liu, Pengyuan et al. (2011) Haplotype association mapping of acute lung injury in mice implicates activin a receptor, type 1. Am J Respir Crit Care Med 183:1499-509
Gao, Song; Yang, Zhen; Yin, Taijun et al. (2011) Validated LC-MS/MS method for the determination of maackiain and its sulfate and glucuronide in blood: application to pharmacokinetic and disposition studies. J Pharm Biomed Anal 55:288-93
Yang, Zhen; Gao, Song; Yin, Taijun et al. (2010) Biopharmaceutical and pharmacokinetic characterization of matrine as determined by a sensitive and robust UPLC-MS/MS method. J Pharm Biomed Anal 51:1120-7
Wang, Yian; Wen, Weidong; Yi, Yijun et al. (2009) Preventive effects of bexarotene and budesonide in a genetically engineered mouse model of small cell lung cancer. Cancer Prev Res (Phila) 2:1059-64
Wang, Yian; Zhang, Zhongqiu; Garbow, Joel R et al. (2009) Chemoprevention of lung squamous cell carcinoma in mice by a mixture of Chinese herbs. Cancer Prev Res (Phila) 2:634-40