Cancer chemopreventive activity of a mixture of Chinese herbs (antitumor B) in mouse lung tumor models.
Antitumor B (ATB), also known as Zeng Sheng Ping, is a Chinese herbal mixture composed of six plants. Previously, clinical studies have shown a significant chemopreventive efficacy of ATB against human esophageal and lung cancers. In the present study, A/J mice harboring a dominant-negative p53 and/or heterozygous deletion of Ink4a/Arf and treated with benzo[a]pyrene were used to investigate the chemopreventive effects of ATB on chemically induced lung tumorigenesis. Mice with various genotypes treated with ATB displayed a significant reduction in lung tumor multiplicity and tumor load. Treatment with ATB resulted in an approximately 40% decrease in tumor multiplicity and a 70% decrease in tumor load in both wild-type mice and in mice with a loss of the Ink4a/Arf tumor suppressor genes. Interestingly, ATB decreased tumor multiplicity and volume by 50 and 90%, respectively, in mice with a dominant-negative p53 and in mice with both a p53 mutation and deletion of Ink4a/Arf. Kras2 mutation analysis of the lung tumors revealed that tumors harbored mutations in the 12th codon of Kras2. There were no differences in either the incidence or types of mutations between tumors treated with or without ATB. Oligonucleotide array analysis revealed 284 genes that were differentially expressed in mouse lung tumors as compared to the normal lung, and it was found that 114 out of these 284 genes changed their expression toward the normal levels in tumors treated with ATB. Most of the genes modulated by ATB belong to several cellular signaling pathways, including Notch (Notch homolog 2, manic fringe homolog), growth factor (FGF intracellular-binding protein, PDGFalpha), G protein-Ras-MAPK (MAPK3, MAP3K4, rab3A, Rap1, RSG5, PKCtheta), ubiquitin-proteasome (CDC34, Cullin1, 26S proteasome), and apoptosis (BAD promoter, caspase 3). These results suggest that ATB is an effective chemopreventive against mouse lung tumorigenesis. Furthermore, ATB exhibited an enhanced inhibitory effect in animals harboring genetic alterations (Kras2, p53, and Ink4a/Arf), which are often seen in human lung adenocarcinomas.
Zhang
Zhongqiu
Z
Department of Surgery and The Alvin J Siteman Cancer Center, Campus Box 8109, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA.
Wang
Yian
Y
Yao
Ruisheng
R
Li
Jie
J
Yan
Ying
Y
La Regina
Marie
M
Lemon
William L
WL
Grubbs
Clinton J
CJ
Lubet
Ronald A
RA
You
Ming
M
D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000627:therapeutic use*; D016158:Genes, p53; D011905:Genes, ras; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000517:prevention & control*; D051379:Mice; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D025803:Tumor Suppressor Protein p14ARF / Q000502:physiology
D016588:Anticarcinogenic Agents; C027128:Antitumor B; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004365:Drugs, Chinese Herbal; D025803:Tumor Suppressor Protein p14ARF