Cancer chemopreventive activity of a mixture of Chinese herbs (antitumor B) in mouse lung tumor models

Tuesday, 11/03/2014  |   Reports  |  no comments


Antitumor B (ATB), also known as Zeng Sheng Ping, is a Chinese herbal mixture composed of six plants; Sophora tonkinensis, Polygonum bistorta, Prunella vulgaris, Sonchus brachyotus, Dictamnus dasycarpus, and Dioscorea bulbifera.. 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 Zg, Wang Y, Yao Rs Yan Y et al. Oncogene (2004) 23, 3841–50. doi:10.1038/sj.onc.1207496 Published online 15 March 2004

Chemoprevention of Lung Squamous Cell Carcinoma in Mice by a Mixture of Chinese Herbs
Anti-tumor B (ATB) is a Chinese herbal mixture of six plants. Previous studies have shown significant chemopreventive efficacy of ATB against human esophageal and lung cancers.
We have recently developed a new mouse model for lung squamous cell carcinomas (SCC). In this study, lung SCC mouse model was characterized using small-animal imaging techniques (MRI and CT). ATB decreased lung SCC significantly (3.1 fold, p < 0.05) and increased lung hyperplastic lesions by 2.4 fold (p < 0.05). This observation suggests that ATB can block hyperplasia from progression to SCC. ATB tissue distribution was determined using matrine as a marker chemical. We found that ATB is rapidly absorbed and then distributes to various tissues including the lung.
These results indicate that ATB is a potent chemopreventive agent against the development of mouse lung squamous cell carcinomas.
Previously, Zhang et al., (2004-above) demonstrated that ATB displayed a significant reduction in B(a)P – induced lung tumor multiplicity and tumor load in wild type mice, mice harboring a dominant-negative p53, mice with heterozygous deletion of Ink4a/Arf, and mice with compound mutations (10). Taken together, these results provide important scientific evidence in support of clinical chemoprevention trials of ATB in patients with precancerous lesions of non small cell lung cancer. This is because few agents that have proven useful in preventing lung cancer to date. ATB is a promising candidate, since it has been shown to inhibit effectively progression of precancerous lesions of human esophagus (dysplasia) to esophageal SCC (Lin et al., 1990).
Lin P, Zhang J, Rong Z, et al. Studies on medicamentous inhibitory therapy for esophageal precancerous lesions–3- and 5-year inhibitory effects of antitumor-B, retinamide and riboflavin. Proc Chin Acad Med Sci Peking Union Med Coll. 1990;5:121–9.
Wang Y, Zhang Zq, Garbow JR, et al. Cancer Prev Res (Phila). Jul 2009; 2(7): 634–640 doi: 10.1158/1940-6207.CAPR-09-0052

Effects of Zeng Sheng Ping/ACAPHA on malignant brain tumor growth and Notch signaling.
Zeng Sheng Ping (ZSP) is a traditional herbal remedy used to prevent progression and growth of neoplastic lesions. It has been shown to inhibit Notch2 expression in a murine lung cancer model, leading us to investigate its therapeutic potential in Notch-dependent brain tumors.
3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS), apoptosis, and quantitative real-time polymerase chain reaction (RT-PCR) analyses were performed in glioma and medulloblastoma cell lines, and morphological analyses in DAOY flank xenografts.
ZSP inhibited brain tumor growth in vitro, in part, by apoptotic induction. Down-regulation of the Notch2 receptor, the pathway target Hairy/Enhancer of Split homolog 1 (Hes1), and of the stem cell markers Nestin and CD133 was also observed. Reductions in tumor mass and increases in the necrotic fraction of DAOY xenografts, in mice treated with oral ZSP were also observed, but these were not significant.
ZSP can block brain tumor growth and the expression of Notch pathway members and stem cell markers in vitro.
Lim KJ, Rajan K, Eberhart CG. Anticancer Res. 2012 Jul;32(7):2689-96.

Results of phase III clinical trial of zeng sheng-ping in the treatment of patients with esophageal epithelial hyperplasia
Through a multi-center randomized, single blinded and placebo controlled trial to evaluate the therapentic effect of Zeng Sheng-ping (ZSP) on esophageal epithelial hyperplasia in a population with high risk of esophageal cancer.
The residents between 40 and 65 years of age in Ci County of Hebei Province were screened by balloon cytological examinations of the esophagus. Patients with esophageal epithelial hyperplasia were further confirmed by biopsy with esophagoscopy. They were randomly stratified into different arms according to sex, age and the grade of hyperplastic lesions. A total of 449 with esophageal epithelial hyperplasia were eligible and randomized into ZSP group and placebo group. In ZSP group, 300 patients received oral ZSP 8 tablets, twice a day for 6 months. There were 149 patients, in the placebo group. To ensure the accuracy of the trial, riboflavin was added into ZSP and placebo group as an indicator of compliance and urine samples were periodically examined.
After 6 months of treatment, the response rate was 64.4% (193/300) in ZSP group and 22.8% (34/149) in the placebo group. There was a statistically significant difference between the two groups(P < 0.001). In addition, the frequency of disease progression in ZSP group was 3.3% (10/300) while that in the placebo group was 24.8% (P < 0.001).
ZSP is an effective drug in the treatment of esophageal epithelial hyperplasia. Adverse effects are mild and well tolerated by the patients.
Wang J. Collaborative group for phase III clinical trial of Zeng Sheng-ping. Zhonghua Zhong Liu Za Zhi. 2000 Nov;22(6):510-2.

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