1.Chemoprevention of Mammary, Cervix and Nervous system Carcinogenesis in Animals using Cultured Panax ginseng Drugs and Preliminary Clinical Trials in Patients with Precancerous Lesions of the Esophagus and Endometrium.
Vladimir G BESPALOV ; Valeriy A ALEXANDROV ; Andrey Y LIMARENKO ; Boris O VOYTENKOV ; Valeriy B OKULOV ; Mels K KABULOV ; Alexander P PERESUNKO ; Larisa I SLEPYAN ; Viktor V DAVYDOV
Journal of Korean Medical Science 2001;16(Suppl):S42-S53
The anticarcinogenic effects and mechanisms of the biotechnological drugs of Panax ginseng C.A. Meyer cultivated in Russia, bioginseng, panaxel and panaxel- 5, were studied. Bioginseng was produced from a tissue culture of ginseng root cultured on standard medium, whereas panaxel and panaxel-5 were produced from ginseng tissue root cultures using standard mediums enriched with 2-carboxyethylgermanium sesquioxide and 1-hydroxygermatran-monohydrate respectively. All three ginseng drugs inhibited the development of mammary tumors induced by intramammary injections of N-methyl-N-nitrosourea (MNU) in rats, the development of the brain and spinal cord tumors induced by transplacental administration of N-ethyl-N-nitrosourea (ENU) in rats, and the development of uterine, cervical and vaginal tumors induced by intravaginal applications of 7,12-dimethylbenz(a)anthracene (DMBA) in mice. The ginseng drugs induced the cytotoxic activity of macrophages in mice, enhanced T-lymphocyte rosette formation in guinea pigs exposed to cyclophosphamide, and stimulated the production of thyroid hormones in rats. These mechanisms may contribute to the anticarcinogenic action of the ginseng drugs. The organic germanium compounds present in panaxel and panaxel-5 did not potentiate the anticarcinogenic or immuno- stimulatory effects as much as biogeinseng. Preliminary clinical trials with panaxel and bioginseng were carried out in patients with precancerous lesions of the esophagus and endometrium. Panaxel was found to have a strong therapeutic effect in patients suffering from chronic erosive esophagitis. Bioginseng induced the regression of adenomatous-cystic hyperplasia of the endometrium in some patients. Thus, we conclude that the drugs of ginseng appear to hold considerable promise for future cancer chemoprevention.
Adenocarcinoma/chemically induced/prevention & control
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Adult
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Animal
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Antineoplastic Agents, Phytogenic/*therapeutic use
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Cells, Cultured
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Cervix Neoplasms/chemically induced/prevention & control
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Clinical Trials
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Cytotoxicity Tests, Immunologic
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Disease Models, Animal
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Endometrial Neoplasms/pathology/prevention & control
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Endometrium/pathology
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Esophageal Neoplasms/pathology/prevention & control
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Esophagus/pathology
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Estradiol/blood
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Female
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Fibroadenoma/chemically induced/prevention & control
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Human
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Macrophages, Peritoneal/cytology/immunology
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Male
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Mammary Neoplasms, Experimental/chemically induced/prevention & control
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Mice
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Mice, Inbred C57BL
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Neoplasms, Experimental/chemically induced/*prevention & control
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Nervous System Neoplasms/chemically induced/prevention & control
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Panax/*metabolism
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Precancerous Conditions/pathology/*prevention & control
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Rats
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Tissue Culture
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Uterine Neoplasms/chemically induced/prevention & control
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Vaginal Neoplasms/chemically induced/prevention & control
2.Expression of ER alpha in chemically induced MDA-MB-435 cells and its responsiveness to endocrine.
Jiang FAN ; Jin-Song LU ; Wen-Jin YIN ; Wang LEI ; Feng-Ying WU ; Jiong WU ; Yi-Feng HOU ; Da-Qiang LI ; Gen-Hong DI ; Zhen-Zhou SHEN ; Zhi-Min SHAO
Chinese Journal of Oncology 2006;28(12):886-889
OBJECTIVETo investigate the expression of ER alpha in chemically induced, ER alpha-negative human breast cancer MDA-MB-435 cells and its restoration of the responsiveness to endocrine therapy.
METHODSMDA-MB-435 cells were treated with HDAC inhibitor trichostatin A(TSA)and DNMT1 inhibitor 5-AZA-CdR (AZA). The mRNA level of ER alpha, PR and PS2 in treated MDA-MB-435 cells was detected by RT-PCR. The WST-8 (water-soluble tetrazolium salt-8) method was used to analyze the proliferation rate of the cells. Xenograft in female nude mice was used to further explore the change of proliferation rate of treated MDA-MB-435 cells in vivo.
RESULTSAfter treatment with AZA and TSA, mRNA expression of ER alpha, PR and pS2 was up-regulated in MDA-MB-435 cells. The mRNA level of ER alpha was the hightest when MDA-MB-435 cells were treated with 2.5 micromol/L AZA and 100 ng/ml TSA. The treated MDA-MB-435 cells showed different proliferation rate in various media containing different concentration of estrodial. The MDA-MB-435 cells showed down-regulated proliferation rate after treatment with the combination of 2.5 micromol/L AZA and 100 ng/ml TSA, and 4-OH tamoxifen could suppress the growth rate of the induced MD-MBA-435 cells but not the untreated cells. The treated MDA-MB-435 cells showed slower proliferation rate than that of untreated cells in vivo (P <0. 01), and the proliferation rate of the treated MDA-MB-435 cells became lower when the nude mice were deprived of estrogen by castration (P <0. 01).
CONCLUSIONAfter treatment with TSA and AZA, ER alpha-negative MDA-MB-435 cells can express functional ER alpha and regain responsiveness to estrogen both in vitro and in vivo. HDAC inhibitor and DNMT1 inhibitor may play an important role in restoration of sensitivity of ER alpha-negative breast cancers to endocrine therapy.
Animals ; Azacitidine ; analogs & derivatives ; pharmacology ; Breast Neoplasms ; genetics ; pathology ; prevention & control ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; DNA Modification Methylases ; antagonists & inhibitors ; Enzyme Inhibitors ; pharmacology ; Estrogen Receptor alpha ; genetics ; Female ; Gene Expression Regulation, Neoplastic ; drug effects ; Histone Deacetylase Inhibitors ; Humans ; Hydroxamic Acids ; pharmacology ; Mammary Neoplasms, Experimental ; genetics ; pathology ; prevention & control ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Ovariectomy ; RNA, Messenger ; biosynthesis ; genetics ; Receptors, Progesterone ; genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Trefoil Factor-1 ; Tumor Suppressor Proteins ; genetics ; Xenograft Model Antitumor Assays
3.Correlation between antimetastatic action of Ajuga decumbens and expression of MMPs and TIMPs.
Bo PENG ; Rong HE ; Qihua XU ; Jie GAO ; Yanli LU ; Jianrong LI
China Journal of Chinese Materia Medica 2011;36(24):3511-3514
OBJECTIVETo investigate the anticancer and anti-metastatic effect of Ajuga decumbens extraction (HBG) on breast cancer and to clarify the effect of HBG on MMPs and TIMPs.
METHODThe antitumor and antimetastic effect of HBG was determined using orthotopic 4T1 breast cancer mouse model. Western blot analysis was employed to detect the expression of associated proteins in breast cancer metastasis.
RESULTAdministration with 50-200 mg x kg(-1) doses of HBG significantly reduced the tumor weight, tumor volume and numbers of lung tumor nodules in a dose-dependent manner. Tumor metastasis correlated proteins were altered following HBG treatment, MMP-2 and MMP-9 were down-regulated while TIMP-1 and TIMP-2 were up-regulated.
CONCLUSIONHBG showed anticancer and antimetastatic effect towards breast cancer through regulating the expression of MMPs and TIMPs. These data sustain our contention that HBG might be used as a potential therapeutic agent.
Ajuga ; Animals ; Female ; Mammary Neoplasms, Experimental ; chemistry ; drug therapy ; pathology ; Matrix Metalloproteinase 2 ; analysis ; Matrix Metalloproteinase 9 ; analysis ; Metalloproteases ; analysis ; Mice ; Mice, Inbred BALB C ; Neoplasm Invasiveness ; Neoplasm Metastasis ; prevention & control ; Phytotherapy ; Plant Extracts ; therapeutic use ; Tissue Inhibitor of Metalloproteinase-1 ; analysis ; Tissue Inhibitor of Metalloproteinase-2 ; analysis ; Tissue Inhibitor of Metalloproteinases ; analysis
4.LYR71, a derivative of trimeric resveratrol, inhibits tumorigenesis by blocking STAT3-mediated matrix metalloproteinase 9 expression.
Ja Eun KIM ; Hong Sook KIM ; Yong Jae SHIN ; Chang Seok LEE ; Cheolhee WON ; Sin Ae LEE ; Jung Weon LEE ; Youngsoo KIM ; Jae Seung KANG ; Sang Kyu YE ; Myung Hee CHUNG
Experimental & Molecular Medicine 2008;40(5):514-522
Tumor migration/invasion is the main cause of tumor progression and STAT3 is needed to enhance tumor migration/invasion by up-regulating MMP-9. Thus, agents that inhibit STAT3 activation may be used as an anticancer drug. We present herein that 6-methyl-2-propylimino-6, 7-dihydro-5H-benzo [1, 3]-oxathiol- 4-one (LYR71) , a derivative of trimeric resveratrol, has an anticancer activity through inhibition of STAT3 activation. We found that LYR71 suppressed STAT3 activation and inhibited the expression and activity of MMP-9 in RANTES-stimulated breast cancer cells. In addition, LYR71 reduced RANTES-induced MMP-9 transcripts by blocking STAT3 recruitment, dissociating p300 and deacetylating histone H3 and H4 on the MMP-9 promoter. Furthermore, LYR71 inhibited tumor migration/invasion in RANTES-treated breast cancer cells and consequently blocked tumor progression in tumor-bearing mice. Taken together, the results of this study suggest that LYR71 can be therapeutically useful due to the inhibition effect of STAT3-mediated MMP-9 expression in breast cancer cells.
Animals
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Antineoplastic Agents/chemistry/*pharmacology
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Bicyclo Compounds, Heterocyclic/chemistry/*pharmacology
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Blotting, Western
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Breast Neoplasms/genetics/metabolism/pathology
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Cell Line, Tumor
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Cell Movement/drug effects
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Cell Survival/drug effects
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Chromatin Immunoprecipitation
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Female
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Gene Expression/drug effects
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Humans
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Imines/chemistry/*pharmacology
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Immunohistochemistry
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Mammary Neoplasms, Experimental/pathology/prevention & control
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Matrix Metalloproteinase 9/genetics/*metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Molecular Structure
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Phosphorylation/drug effects
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Reverse Transcriptase Polymerase Chain Reaction
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STAT3 Transcription Factor/genetics/*metabolism
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Stilbenes/chemistry
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Xenograft Model Antitumor Assays/methods