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

11th Tuesday, 2014  |   Reports  |  no comments

chinese-herbs.jpg

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.
Source
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).
Reference
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.
Source
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.
Source
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.
Source
Wang J. Collaborative group for phase III clinical trial of Zeng Sheng-ping. Zhonghua Zhong Liu Za Zhi. 2000 Nov;22(6):510-2.

Cancer as a metabolic disease: implications for novel therapeutics

11th Tuesday, 2014  |   Reports  |  no comments

F1.medium
Seyfried TN, Flores RE, Poff AM & D’Agostino DP. Carcinogenesis (2013) doi: 10.1093/carcin/bgt480
Full text available at: http://carcin.oxfordjournals.org/content/early/2014/01/18/carcin.bgt480.full

Emerging evidence indicates that cancer is primarily a metabolic disease involving disturbances in energy production through respiration and fermentation. The genomic instability observed in tumor cells and all other recognized hallmarks of cancer are considered downstream epiphenomena of the initial disturbance of cellular energy metabolism. The disturbances in tumor cell energy metabolism can be linked to abnormalities in the structure and function of the mitochondria. When viewed as a mitochondrial metabolic disease, the evolutionary theory of Lamarck can better explain cancer progression than can the evolutionary theory of Darwin. Cancer growth and progression can be managed following a whole body transition from fermentable metabolites, primarily glucose and glutamine, to respiratory metabolites, primarily ketone bodies. As each individual is a unique metabolic entity, personalization of metabolic therapy as a broad-based cancer treatment strategy will require fine-tuning to match the therapy to an individual’s unique physiology.

Cancer is a disease involving multiple time- and space-dependent changes in the health status of cells and tissues that ultimately lead to malignant tumors. Neoplasia (abnormal cell growth) is the biological endpoint of the disease. Tumor cell invasion into surrounding tissues and their spread (metastasis) to distant organs is the primary cause of morbidity and mortality of most cancer patients. A major impediment in the effort to control cancer has been due in large part to the confusion surrounding the origin of the disease. Contradictions and paradoxes continue to plague the field. Much of the confusion surrounding cancer origin arises from the absence of a unifying theory that can integrate the many diverse observations on the nature of the disease. Without a clear understanding of how cancer arises, it becomes difficult to formulate a successful strategy for effective long-term management and prevention. The failure to clearly define the origin of cancer is responsible in large part for the failure to significantly reduce the death rate from the disease. Although cancer metabolism is receiving increased attention, cancer is generally considered a genetic disease. This general view is now under serious reevaluation. The information in this review comes in part from our previous articles and treatise on the subject.

Advanced metastatic cancers can become manageable when their access to fermentable fuels becomes restricted. The metabolic shift associated with the KD-R involves ‘keto-adaptation’. However, the adaptation to this new metabolic state can be challenging for some people. The administration of ketone esters could conceivably enable patients to circumvent the dietary restriction generally required for sustained nutritional ketosis. Ketone ester-induced ketosis would make sustained hypoglycemia more tolerable and thus assist in metabolic management of cancer. As each person is a unique metabolic entity, personalization of metabolic therapy as a broad-based cancer treatment strategy will require fine-tuning based on an understanding of individual human physiology. Also, personalized molecular therapies developed through the genome projects could be useful in targeting and killing those tumor cells that might survive the non-toxic whole body metabolic therapy.
The number of molecular targets should be less in a few survivor cells of a small tumor than in a heterogeneous cell population of a large tumor. We would therefore consider personalized molecular therapy as a final strategy rather than as an initial strategy for cancer management. Non-toxic metabolic therapy should become the future of cancer treatment if the goal is to manage the disease without harming the patient. Although it will be important for researchers to elucidate the mechanistic minutia responsible for the therapeutic benefits, this should not impede an immediate application of this therapeutic strategy for cancer management or prevention.

Changes of peripheral blood lymphocyte subtypes in patients with end stage cancer administered localized radiotherapy and Bojungikki-Tang (Bu-Zhong-Yi-Qi-Tang)

5th Wednesday, 2014  |   Cancer  |  no comments

Bu-Zhong-Yi-Qi-Tang
Source:
Evidence-Based Complementary and Alternative Medicine. Volume 2014 (2014) http://dx.doi.org/10.1155/2014/207613
Localized radiotherapy (RT) can cause immune dysfunction. Bojungikki-tang (Bu-Zhong-Yi-Qi-Tang in Mandarin) is known to restore immune function. We investigated the absolute counts and percentages of peripheral blood (PB) lymphocyte subtypes in end stage cancer patients before and after RT and after oral administration of Bojungikki-tang water extract (BJITE) and to evaluate the changes mediated by RT and BJITE.
Absolute counts and percentages of lymphocyte and lymphocyte subsets were determined in whole blood using the TetraONE System (Beckman Coulter, USA). Flow cytometry results were compared before and after RT and after administration of BJITE. Absolute numbers of CD3+, CD4+, and CD8+ T cells and CD19+ B cells decreased significantly after RT. Absolute numbers of CD3-CD56+ cells did not change in both groups.
No significant differences were observed in the absolute counts of lymphocyte subtypes before and after administration of BJITE or vitamin group. When BJITE group was compared with vitamin group, absolute numbers of CD19+ B cells increased. RT-induced decrease in T cells and B cells in PB suggests that immune deterioration occurs after RT. Administration of BJITE might be effective in the restoration of number of B cells.
Bojungikki-tang is known to restore immune functions and to improve anti-tumor activity. It is usually indicated for patients with general weakness and anemia. Palliative RT relieves clinical symptoms in advanced cancer patients but it can also cause immunological changes. In the present study, we have investigated the percentages and absolute counts of PB lymphocytes and lymphocyte subtypes in patients with end stage cancer administered localized radiotherapy and Bojungikki-tang.
In our study, total lymphocyte in counts and percentages of lymphocytes did not change after palliative RT in both groups. This is contrast to the results of the earlier study of radiation-induced lymphocytopenia. This is probably due to differences of radiation dose and interval.
Conclusions
In conclusion, RT-induced decrease in helper T cells, cytotoxic T cells, and B cells in PB suggests that immune deterioration occurs after RT. Administration of BJITE might be effective in the restoration of number of B cells.

In Vitro and In Vivo Effects of Jia-Wei-Xiao-Yao-San in Human Breast Cancer MCF-7 Cells Treated With Tamoxifen

14th Friday, 2014  |   Breast Cancer  |  no comments

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There is epidemiological evidence that Jia-Wei-Xiao-Yao-San (JWXYS) is the most common Chinese medicine decoction coprescribed with tamoxifen (Tam) when breast cancer is treated by hormonal therapy. However, whether there is interaction between JWXYS and Tam remains to be clarified. The aim of this study was to investigate the in vitro and in vivo effects of JWXYS on human breast cancer MCF-7 cells treated with Tam.

 

In vitro cultured MCF-7 cells were cotreated with JWXYS and Tam. This was followed by MTT ([4,5-cimethylthiazol-2-yl]- 2,5-diphenyl tetrazolium bromide) assays and cell cycle analysis to assess cell proliferation; Western blot analysis was used to analyze the expression of various proteins involved in growth-related signal pathways. In addition, immunohistochemistry was used to detect autophagy among the cancer cells. In vivo analysis used female athymic nude mice implanted with MCF-7 cells; these mice were randomly assigned to 6 groups. All mice were killed humanely after 21 days of treatment; body weight, tumor volume, and tumor weight were then measured. Results.

 

JWXYS was not cytotoxic to MCF-7 cells, based on the fact that there were no statistically significant changes between the JWXYS + Tam groups and the Tam-alone group in cell numbers, cell cycle progression, and cell proliferation signals, the latter including the expression levels of AKT, ERK, P38, p27(Kip1), and light chain (LC3)-I, II. Furthermore, using the MCF-7 xenograft mouse model, there were no significant changes between the JWXYS (1.3-3.9 gm/kg) + Tam groups and the Tam-alone group in terms of tumor weight and the protein expression levels of AKT, ERK, P38, and p27 (Kip1).

 

However, there was a significant decrease in LC3-II protein expression with the low-dose JWXYS + Tam group but not with the middle- or high-dose JWXYS + Tam groups compared with the Tam-alone group.

 

Based on in vitro studies and in vivo functional studies, there is no obvious interaction between JWXYS and Tam. However, the presence of interference at the molecular level in relation to LC3-II expression provides important information and may affect treatment strategies when physicians have patients with estrogen receptor-α(+) or progesterone receptor(+) breast cancers.

 

Source:

Integr Cancer Ther February 12, 2014 doi: 10.1177/1534735414520970

Clinical significance of macrophage heterogeneity in human malignant tumors with articles on down-regulating VEGF

28th Tuesday, 2014  |   Others  |  no comments

PastedGraphic-11

It has long been known that many leukocytes including macrophages are present in tumor tissues and that these cells, together with fibroblasts and vascular endothelial cells, form the tumor microenvironment.[1-4] Previously, activated macrophages were believed to exhibit antitumor activity by directly attacking tumor cells in the tumor microenvironment.[5] However, many recent studies have indicated the protumoral functions of tumor-associated macrophages (TAMs), and thus, TAMs are believed to directly or indirectly promote tumor progression.[6-8] Great advances have been made in TAM research over the past dozen years or so, with one of the most significant breakthroughs being the development of immunohistochemical methods for identifying TAMs in tumor tissue. Numerous studies using human samples have been carried out using CD68 as a macrophage marker, whereas CD163 and CD204 have been used as markers of M2 macrophages in recent studies.[9, 10] Although variability is observed according to tumor tissue type and location, over 80% of immunohistochemical studies using various human tumor tissues have shown that higher numbers of TAMs are associated with worse clinical prognosis.[9] Supporting these clinical observations, in vitro experiments using human tumor cells and experiments using animal models indicate that TAMs promote tumor cell growth by suppressing antitumor immunity and inducing angiogenesis.[11, 12]

 

TAMs promote tumor progression through induction of angiogenesis and suppression of antitumor immunity. In particular, in humans, protumoral TAMs are believed to exhibit characteristics similar to M2 macrophages, and are intimately involved in the progression of malignant tumors. As such, treatment strategies aimed at local inhibition of macrophage differentiation into the M2 phenotype are anticipated to be effective. Signal transduction pathways, including nuclear factor (NF)-?B, Stat3, Stat6, c-Myc, and interferon regulatory factor 4, are involved in differentiation into the M2 phenotype.[13, 14-16] Nuclear factor-?B and Stat3 are also strongly involved in tumor cell growth, and drugs targeting these molecules are currently being developed. Among such molecule-specific drugs, synergistic efficacy due to direct effects on tumor cells, as well as inhibition of the differentiation of TAMs into the M2 phenotype, is expected. Among drugs currently in use, some are active against TAMs. Cyclosporin A and trabectedin not only directly inhibit tumor cell growth, they also suppress activation of TAMs.[17] Bisphosphonates not only suppress bone resorption by osteoclasts, they also inhibit the differentiation of TAMs into the M2 phenotype. The angiogenic inhibitor bevacizumab (a VEGF-inhibiting antibody) has recently been used to treat solid tumors such as colorectal adenocarcinoma, and this drug also exhibits antitumor activity by suppressing TAM migration.[18]

 

Source

Komohara Y et al. Cancer Science. Volume 105, Issue 1, pages 1–8, January 2014. DOI: 10.1111/cas.12314

 

References

1. Monis B, Weinberg T. Cytochemical study of esterase activity of human neoplasms and stromal macrophages. Cancer 1961; 14: 369–77.

2. Underwood JC, Carr I. The ultrastructure of the lymphoreticular cells in non-lymphoid human neoplasms. Virchows Arch B Cell Pathol 1972; 12: 39–50.

3. Lauder I, Aherne W, Stewart J, Sainsbury R. Macrophage infiltration of breast tumours: a prospective study. J Clin Pathol 1977; 30: 563–8.

4. Kreutz M, Fritsche J, Andreesen R. Macrophages in tumor biology. In; Burke B, Lewis CE, eds. The Macrophage, 2nd edn. Oxford, UK: Oxford Univ. Press, 2002; 458–89.

5. Tagliabue A, Mantovani A, Kilgallen M, Herberman RB, McCoy JL. Natural cytotoxicity of mouse monocytes and macrophages. J Immunol 1979; 122: 2363–70.

6. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 2002; 23: 549–55.

7. Bingle L, Brown NJ, Lewis CE. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol 2002; 196: 254–65.

8. Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 2004; 4: 71–8.

9. Heusinkveld M, van der Burg SH. Identification and manipulation of tumor associated macrophages in human cancers. J Transl Med 2011; 9: 216.

10. Komohara Y, Ohnishi K, Kuratsu J, Takeya M. Possible involvement of the M2 anti-inflammatory macrophage phenotype in growth of human gliomas. J Pathol 2008; 216: 15–24.

11. Sica A, Schioppa T, Mantovani A, Allavena P. Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer 2006; 42: 717–27.

12. Yu H, Kortylewski M, Pardoll D. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol 2007; 7: 41–51.

13. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 2012; 122: 787–95.

14. Pello OM, De Pizzol M, Mirolo M et al. Role of c-MYC in alternative activation of human macrophages and tumor-associated macrophage biology. Blood 2012; 119: 411–21.

15. Satoh T, Takeuchi O, Vandenbon A et al. The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat Immunol 2010; 11: 936–44.

16. Lawrence T, Natoli G. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol 2011; 11: 750–61.

17. Germano G, Frapolli R, Belgiovine C et al. Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell 2013; 23: 249–62.

18. Roland CL, Dineen SP, Lynn KD et al. Inhibition of vascular endothelial growth factor reduces angiogenesis and modulates immune cell infiltration of orthotopic breast cancer xenografts. Mol Cancer Ther 2009; 8: 1761–71.

 

HERBS AND COMPOUND, WHICH INHIBIT/DOWNREGULATE VEGF

Vascular abnormalities inside tumors are important factors resulting in abnormal tumor microenvironment. Microenvironment was closely correlated with the malignant degrees, metastasis, and recurrence of tumors. Besides, the acid environment, oxygen deficiency, and other factors it induced may severely affect the efficacies of routine therapies, radiotherapy and chemotherapy. Anti-angiogenesis treatment drugs targeting vascular endothelial growth factor (VEGF) not only antagonize the angiogenesis of tumor vessels, but also promote the vascular normalization inside tumors to some extent, thus reducing interstitial hypertension, improving blood flow inside tumors, and enhancing therapeutic efficacies. Previous clinical and experimental studies have proved that many Chinese herbs show enhancing effects of chemotherapy and radiotherapy in comprehensive treatment of chemotherapy and radiotherapy combination. Meanwhile, recent studies have also proved that many Chinese herbs could fight against tumor vascular angiogenesis, lower serum VEGF concentration, and inhibit expressions of VEGF. Therefore, studying Chinese herbs’ mechanisms of anti-tumor from promoting vascular normalization will open up a brand new field for seeking a cut-in point for Chinese medicine therapy in the comprehensive treatment, optimizing a treatment protocols, and further clarifying the roles of Chinese medicine in the comprehensive treatment.Source

Source

You J. Study on the tumor microenvironment and tumor vascular normalization in integrative treatment of tumor by Chinese medicine and western medicine. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2011 Aug;31(8):1127-31.

Medicinal herbs and their phytochemicals are potential novel leads for developing antiangiogenic drugs. This review aims to assess the current status of research with medicinal herbs and their phytochemicals for the development of antiangiogenic agents for cancer and other angiogenesis-related diseases including inflammation, diabetic retinopathy, endometriosis and obesity. Most studies reviewed have focused on vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor 2 (VEGFR-2) signaling for endothelial response processes and have led to the identification of many potential antiangiogenic agents. Since human clinical trials with antiangiogenic modalities targeting VEGF/VEGFR-2 signaling have shown limited efficacy and occasional toxic side effects, screening strategies for herbal phytochemicals based on other signaling pathways important for cancer-endothelial and stromal crosstalks should be emphasized in the future.

Source

Jeong SJ, Koh W, Lee EO, Lee HJ, Lee HJ, Bae H, Lü J, Kim SH. Antiangiogenic phytochemicals and medicinal herbs. Phytother Res. 2011 Jan;25(1):1-10. doi: 10.1002/ptr.3224. DOI: 10.1002/ptr.3224

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