• Archives of Pharmacal Research
• /
• v.22 no.2
• /
• pp.173-178
• /
• 1999

Remarks on polyphenolic compounds has been arisen since past few years. the flavonoids appears to be the important groups of compounds with their capability to inhibit DNA damage, lipid peroxidation, to quench free radicals and, at least, anticarcinogenic and antiproliferative effects. On the other hand, their mechanism of action is still unexplained. Apigenin and luteolin are the most wide-spread flavones and they exhibited to be useful in chemoprevention. UV spectrometric and DC polarographic studies on these two compounds have been carried out with regard to changing pH. The most significant changes were observed at basic pH. These results could aid to elucidation of their mechanism of action as pH is one of the important factors for bioprocesses passing in living organisms.

• BMB Reports
• /
• v.36 no.1
• /
• pp.43-48
• /
• 2003

Understanding the process of carcinogenesis will involve both the accumulation of many scientific facts derived from molecular, biochemical, cellular, physiological, whole animal experiments and epidemiological studies, as well as from conceptual understanding as to how to order and integrate those facts. From decades of cancer research, a number of the "hallmarks of cancer" have been identified, as well as their attendant concepts, including oncogenes, tumor suppressor genes, cell cycle biochemistry, hypotheses of metastasis, angiogenesis, etc. While all these "hallmarks" are well known, two important concepts, with their associated scientific observations, have been generally ignored by many in the cancer research field. The objective of the short review is to highlight the concept of the role of human adult pluri-potent stem cells as "target cells" for the carcinogenic process and the concept of the role of gap junctional intercellular communication in the multi-stage, multi-mechanism process of carcinogenesis. With these two concepts, an attempt has been made to integrate the other well-known concepts, such as the multi-stage, multi-mechanisn or the "initiation/promotion/progression" hypothesis; the stem cell theory of carcinogenesis; the oncogene/tumor suppression theory and the mutation/epigenetic theories of carcinogenesis. This new "integrative" theory tries to explain the well-known "hallmarks" of cancers, including the observation that cancer cells lack either heterologous or homologous gap junctional intercellular communication whereas normal human adult stem cells do not have expressed or functional gap junctional intercellular communication. On the other hand, their normal differentiated, non-stem cell derivatives do express connexins and express gap junctional intercellular communication during their differentiation. Examination of the roles of chemical tumor promoters, oncogenes, connexin knock-out mice and roles of genetically-engineered tumor and normal cells with connexin and anti-sense connexin genes, respectively, seems to provide evidence which is consistent with the roles of both stem cells and gap junctional communication playing a major role in carcinogenesis. The integrative hypothesis provides new strategies for chemoprevention and chemotherapy which focuses on modulating connexin gene expression or gap junctional intercellular communication in the premalignant and malignant cells, respectively.

• Korean Journal of Plant Resources
• /
• v.30 no.6
• /
• pp.640-646
• /
• 2017

In this study, we elucidated anti-cancer activity and potential molecular mechanism of 70% ethanol extracts from Taxilli Ramulus (Taxillus chinensis (DC.) Danser) (TR-E70) against human colorectal cancer cells. Anti-cell proliferative effect of TR-E70 was evaluated by MTT assay. The effect of TR-E70 on the expression of cyclin D1 in the protein and mRNA level was evaluated by Western blot and RT-PCR, respectively. TR-E70 suppressed the proliferation of human colorectal cancer cell lines, HCT116 and SW480. Although TR-E70 decreased cyclin D1 expression in protein and mRNA level, decreased level of cyclin D1 protein by TR-E70 more dramatically occurred than that of cyclin D1 mRNA. Cyclin D1 downregulation by TR-E70 was attenuated in presence of MG132. In addition, TR-E70 phosphorylated threonine-286 (T286) of cyclin D1. TR-E70-mediated cyclin D1 degradation was blocked in presence of LiCl as an inhibitor $GSK3{\beta}$ but not PD98059 as an ERK1/2 inhibitor and SB203580 as a p38 inhibitor. Our results suggest that TR-E70 may downregulate cyclin D1 as one of the potential anti-cancer targets through $GSK3{\beta}$-dependent cyclin D1 degradation. From these findings, TR-E70 has potential to be a candidate for the development of chemoprevention or therapeutic agents for human colorectal cancer.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
• /
• v.26 no.2
• /
• pp.137-145
• /
• 2000

Carcinogenesis is a multi-stage process that generally consists of at least three steps; initiation, promotion, and progression. If one of these carcinogenic steps were suppressed or delayed, the cancer could be prevented. Cancer chemoprevention is defined to be inhibition or reversal of the carcinogenic process by the specific chemical agents and is a novel approach to cancer management alternative to conventional chemotherapy. Chlorophylln(CHL), a water-soluble derivative of chlorophyll, containing sodium and copper, has been known to be strong antimutagen in several test systems, but its mechanism of antimutagenic action is unknown. In the present experiment, the possibility of CHL as chemopreventive drugs on 7,12-dimethylbenz[a]anthracene(DMBA)-induced hamster buccal pouch carcinogenesis was investigated by mutagenicity test, carcinogenicity test, and frequency or spectrum of H-ras mutations in the both of DMBA-induced and chlorophylln-pretreated-DMBA induced tumor by polymerase chain reaction and non-isotopic restriction fragment length polymorphism. The treatment of CHL reduced the yields and multiplicity of the 0.5% DMBA-induced tumor, 86% to 62.5% and $3.7{\pm}0.6$ to $1.4{\pm}0.3$, respectively. The occurrence of histidine revertant by $20{\mu}mole$ DMBA was inhibited 25.6 to 81.7% by 1 to $5{\mu}M$ CHL in a dose-dependent manner. The mutation rates of H-ras gene in DMBA-induced and CHL-pretreated-DMBA induced tumor were 96%, 94% of which the most mutations were in codon 12/13. These results suggest that CHL inhibits the carcinogenic action of DMBA by the formation of complex between CHL and DMBA or the inhibition of the activation of DMBA in vivo. But CHL did not affect the mutation rates or its spectrum in already formed tumor.

• Biomolecules & Therapeutics
• /
• v.20 no.6
• /
• pp.499-505
• /
• 2012

Chemoprevention represents a strategy designed to protect cells or tissues against various carcinogens and carcinogenic metabolites derived from exogenous or endogenous sources. Recent studies indicate that plant-derived triterpenoids, like oleanolic acid, may exert cytoprotective functions via regulation of the activity of different transcription factors. The chemopreventive effects may be mediated through induction of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor. Activation of Nrf2 by triterpenoids induces the expression of phase 2 detoxifying and antioxidant enzymes such as NAD(P)H quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1) - proteins which can protect cells or tissues against various toxic metabolites. On the other hand, inhibition of other transcription factors, like NF-${\kappa}B$ leads to the decrease in the pro-inflammatory gene expression. Moreover, the modulation of microRNAs activity may constitute a new mechanism responsible for valuable effects of triterpenoids. Recently, based on the structure of naturally occurring triterpenoids and with involvement of bioinformatics and computational chemistry, many synthetic analogs with improved biological properties have been obtained. Data from in vitro and in vivo experiments strongly suggest synthetic derivatives as promising candidates in the chemopreventive and chemotherapeutic strategies.

• Current Research on Agriculture and Life Sciences
• /
• v.32 no.3
• /
• pp.119-124
• /
• 2014

Physalis alkekengi var. francheti Hort. is known as an insecticide and traditional remedy for liver related diseases. Therefore, this study investigated the chemopreventive effects of extracts and several solvent fractions (n-hexane, dichloromethane, n-butanol, water) of Physalis alkekengi var. francheti Hort. First, their cytotoxicity and NQO1 activity were measured using an MTT assay, plus a quinone reductase [NAD(P)H dehydrogenase (quinone); NAD(P)H: (quinone acceptor) oxidoreductase, EC 1.6.99.2]-inducing activity assay was performed using cultured murine hepatoma cells (Hepa1c1c7) and its mutant cells(BpRc1). The reduction of electrophilic quinones by NQO1 is an important detoxification pathway and major mechanism of chemoprevention. When compared with the other solvent soluble fractions with different polarities, the dichloromethane fraction of Physalis alkekengi var. francheti Hort. showed a higher NQO1-inducing activity that was also dose-dependent. Moreover, the dichloromethane fraction of Physalis alkekengi var. francheti Hort. induced ARE-luciferase activities in HepG2-C8 cells that were generated by transfecting the ARE-luciferase gene construct, suggesting the Nrf2-ARE-mediated induction of anti-oxidative enzymes. In conclusion, the dichloromethane-soluble fraction of Physalis alkekengi var. francheti Hort. showed a relatively strong induction of detoxifying enzymes, thereby meriting further study to identify the active components and evaluate their potential as cancer preventive agents.

• Journal of Gastric Cancer
• /
• v.2 no.2
• /
• pp.73-80
• /
• 2002

In spite the fact that H. pylori infection might be the causative organisms of acute and chronic gastritis, peptic ulcer diseases and the definition as the class I carcinogen by WHO IARC, still debates exist about the relationship between H. pylori and gastric carcinogenesis. Epidemiological and animal studies demonstrated a link between gastric cancer and chronic infection with H, pylori, but the exact mechanism responsible for the development of gastric cancer in H. pylori-infected patients still remain obscure. In order to declare the clear association, definate evidences like that decrement in the incidence of gastric cancer after the eradication of H. pylori in designated area compared to noneradicated region or the blockade of specific mechanism acting on the carcinogenesis by H. pylori infection. The other way is to identify the upregulating oncogenes or downregulating tumor suppressor genes specifically invovled in H. pylori-associated carcinogenesis. For that, we established the animal models using C57BL/6 mice strain. Already gastric carcinogenesis was developed in Mongolian gerbils infected with H. pylori, but there has been no development of gastric cancer in mice model infected with H. pylori after long-term evaluation. Significant changes such as atrophic gastritis were observed in mice model. However, we could observe the development of mucosal carcinoma in the stomach of transgenic mice featuring the loss of TGF-beta sig naling by the expressions of dominant negative forms of type II receptor specifically in the stomach. Moreover, the incidence of gastric adenocarcinoma was significantly increased in group administered with both MNU and H. pylori infection than MNU alone, signifying that H. pylori promoted the gastric carcinogenesis and there might be host susceptibility genes in H. pylori-associated gastric carcinogenesis. Based on the assumption that chronic, uncontrolled inflammation might predispose to carcinogenesis, there have been several evidences showing chronic atrophic gastritis predisposed to gastric carcinogenesis in H. pylori infection. Although definite outcome of chemoprevention was not drawn after the longterm administration of anti-inflammatory drug in H. pylori infection, the actual incidence of atrophic gastritis and molecular evidence of chemoprevention could be obtained. Selective COX-2 inhibitor was effective in decreasing the development of gastric carcinogenesis provoked by H. pylori infection and carcinogen like in chemoprevention of colon carcinogenesis.

• Biomolecules & Therapeutics
• /
• v.24 no.4
• /
• pp.380-386
• /
• 2016

Silymarin from milk thistle (Silybum marianum) has been reported to show an anti-cancer activity. In previous study, we reported that silymarin induces cyclin D1 proteasomal degradation through NF-${\kappa}B$-mediated threonine-286 phosphorylation. However, mechanism for the inhibition of Wnt signaling by silymarin still remains unanswered. Thus, we investigated whether silymarin affects Wnt signaling in human colorectal cancer cells to elucidate the additional anti-cancer mechanism of silymarin. Transient transfection with a TOP and FOP FLASH luciferase construct indicated that silymarin suppressed the transcriptional activity of ${\beta}$-catenin/TCF. Silymarin treatment resulted in a decrease of intracellular ${\beta}$-catenin protein but not mRNA. The inhibition of proteasome by MG132 and $GSK3{\beta}$ inhibition by SB216763 blocked silymarin-mediated downregulation of ${\beta}$-catenin. In addition, silymarin increased phosphorylation of ${\beta}$-catenin and a point mutation of S33Y attenuated silymarin-mediated ${\beta}$-catenin downregulation. In addition, silymarin decreased TCF4 and increased Axin expression in both protein and mRNA level. From these results, we suggest that silymarin-mediated downregulation of ${\beta}$-catenin and TCF4 may result in the inhibition of Wnt signaling in human colorectal cancer cells.

• Asian Pacific Journal of Cancer Prevention
• /
• v.14 no.11
• /
• pp.6863-6867
• /
• 2013

Phyllanthus emblica (PE) is known to exhibit various pharmacological properties. This study aimed to evaluate the antimetastatic potential of a PE aqueous extract. Cytotoxicity to human fibrosarcoma cells, HT1080, was determined by viability assay using the 3-(4,5-dimethylthiazol,2-yl)-2,5-diphenyltetrazolium bromide (MTT) reagent. Cell migration and invasion were investigated using chemotaxis chambers containing membranes precoated with collagen IV and Matrigel, respectively. Cell attachment onto normal surfaces of cell culture plates was tested to determine the cell-adhesion capability. The molecular mechanism of antimetastatic activity was assessed by measuring the gene expression of matrix metalloproteinases, MMP2, and MMP9, using reverse transcription-polymerase chain reaction (RT-PCR) assay. The mRNA levels of both genes were significantly down-regulated after pretreatment with PE extract for 5 days. Our findings show the antimetastatic function of PE extract in reducing cell proliferation, migration, invasion, and adhesion in both dose- and time-dependent manners, especially growth arrest with low $IC_{50}$ value. A decrease in the expression of both MMP2 and MMP9 seems to be the cellular mechanism for antimetastasis in this case. There is a high potential to use PE extracts clinically as an optional adjuvant therapeutic drug for therapeutic intervention strategies in cancer therapy or chemoprevention.

• Archives of Pharmacal Research
• /
• v.29 no.2
• /
• pp.165-171
• /
• 2006

Osteoarthritis is thought to be induced by the ageing-related loss of homeostatic balance between degeneration and repair mechanism around cartilage tissue in which inflammatory mediators such as reactive oxygen species, cytokines and prostaglandins are prone to overproduction under undesirable physiological conditions. Phlorotannins are unique polyphenolic compounds bearing dibenzo-1,4-dioxin skeleton which are not found in terrestrial plants but found only in some brown algal species such as Ecklonia and Eisenia families. Phlorotanninrich extracts of Ecklonia cava including LAD103 showed significant antioxidant activities such as DPPH radical scavenging, ferric ion reduction, peroxynitrite scavenging, and inhibition of LDL oxidation, indicating their possible antioxidative interference both in onset and downstream consequences of osteoarthritis. LAD103 also showed significant down regulation of $PGE_2$ generation in LPS-treated RAW 246.7 cells, and significant inhibition of human recombinant interleukin-$1{\alpha}$-induced proteoglycan degradation, indicating its beneficial involvement in pathophysiological consequences of osteoarthritis, the mechanism of which needs further investigation. Since LAD103 showed strong therapeutic potentials in arthritic treatment through several in vitro experiments, it is highly encouraged to perform further mechanistic and efficacy studies.