• Proceedings of the Korean Society of Toxicology Conference
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• 2002.05b
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• pp.88.2-98
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• 2002

A wide arry of naturally occurring substances particularly those present in dietary and medicinal plants, have been reported to possess substantial cancer chemopreventive properties. Certain phytochemicals retain strong antioxidative and anti-inflammatory properties which appear to contribute to their chemopreventive or chemoprotective activities. Inducible cyclooxygenase(COX-2) and nitric oxide synthase (iNOS) are important enzymes that mediate inflammatory processes. There is some evidence that expression of both COX-2 and iNOS is co-regulated by the eukaryotic transcription factor NF-$textsc{k}$B. Increased expression of COX-2 and/or iNOS has been associated with pathophysiology of certain types of human cancers as well as inflammatory diseases. Since inflammation is closely linked to tumor promotion, substances with potent anti-inflammatory activies are anticipated to exert chemopreventive effects on carcinogenesis, particularly in the promotion stage. An example is curcumin, a yellow pigment of turmeric (Curcuma longa L., Zingiberaceae), that strongly occurring diaryl heptanoids structurally related to curcumin have substantial anti-tumor promotional activities in two-stage mouse skin carcinogenesis. Thus, yakuchinone A [1-(4'-hydroxy-3'-methoxyphenyl)-7-phenyl-3heptanone] and yakuchinone B [1-(4'-hydroxy-3'methoxyphenyl)-7-phenylhept-1-en-3-one] present in Alpinia oxyphylla Miquel (Zingiberacease) attenuate phorbol ester-induced inflammation and papilloma formation in female ICR mice. These diarylheptanoids also suppressed phorbol ester-induced activation of epdermal ornithine decarboxylase and its mRNA expression when applied onto shaven backs of mice. Yakuchinone A and B as well as curcumin inhibited phorbol ester-induced expression of COX-2 and iNOS and their mRNA in mouse skin via inactivation of NF-$textsc{k}$B. Capsaicin, a major pungent ingredient of red pepper also attenuated phorbol ester-induced NF-$textsc{k}$B activation. Similar suppression of COX-2 and iNOS and down-regulation of NF-$textsc{k}$B activation for its DNA binding were observed with the ginsenosied Rg3 and the ethanol extract of Artemisia asiatica. We have also found that certain anti-inflammatory phytochemicals exert inhibitory effects on phorbol ester-induced COX-2 expression and NF-$textsc{k}$B activation in immortalized human breast epithelial (MCF-10A) cells in culture. One of the plausible mechanisms undelying inhibition by aforementioned phytochemicals of phorbol ester-induced NF-$textsc{k}$B activation involves interference with degragation of the inhibitory unit, I$textsc{k}$Ba, which blocks subsequent nuclear translocation of the functionally active p65 subunit of NF-$textsc{k}$B. the activation of epidermal NF-$textsc{k}$B by phorbol ester and subsequent induction of COX-2 hence appear to play an important role in intracellular signaling pathwasy leading to tumor promotion and targeted inhibition of NF-$textsc{k}$B may provide a new promising cancer chemopreventive strategy.

• Environmental Mutagens and Carcinogens
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• v.21 no.2
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• pp.164-168
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• 2001

Abel et al. in Germany discovered a new dioxin-responsive gene, which has later been identified as rpt-1 (regulatory protein T-lymphocyte 1). While it is speculated that rpt-1 may play a role in signal transduction and carcinogenesis, its roles and functions remain unknown. The present study attempted to analyze functions of rpt-1 in human epithelial cells following the xenobiotic exposures. While German counterpart analyzed expressionn of rpt-1 in spleen and thymus cells from mouse and rat and characterizes molecular properties of the gene, our work mainly focused on analyzing function of rpt-1 in human skin cells. Expression of rpt-1 in human cells were analyzed by western and northern blot RT-PCR analysis. Expression of rpt-1 as well as Staf-50 in human cells with or without exposure to environmental pollutants were also analyzed by northern blot analysis, since Staf-50 is homologous with rpt-1 and found in human cells. To help study roles of rpt-1 in human cell system, retroviral vector system carrying rpt-1 gene under the CMV promoter were constructed and transfected. Cells overexpressing the gene after the transfection showed an increase of cell density and soft agar colony formations, as compared to the control cells, suggesting that rpt-1 may play a certain role in the transformation processes of human cells. While the expression of rpt-1 in spleen and thymus is known to be strong in the laboratory animals, both the basal and TCDD-induced expression of rpt-1 in the current cellular system remained insignificant. It is speculated that the expression pattern of rpt-1 may be tissue- and species-specific. The present study demonstrated a strong expression of rpt-1 protein in the brain of SD rat model. Since there is no previous report on the expression of rpt-1 in the brain tissue, the result may play a significant role in understanding dioxin-induced neurotoxicities in the future. The present study provides an opportunity to understand a role of rpt-1 in human cell system and suggest a possible lead and basis for the future study of dioxin-induced neurotoxicities.

• Molecules and Cells
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• v.39 no.3
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• pp.266-279
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• 2016

The mechanism by which 12-O-tetradecanoylphorbol-13-acetate (TPA) bypasses cellular senescence was investigated using human diploid fibroblast (HDF) cell replicative senescence as a model. Upon TPA treatment, protein kinase C (PKC) ${\alpha}$ and $PKC{\beta}1$ exerted differential effects on the nuclear translocation of cytoplasmic pErk1/2, a protein which maintains senescence. $PKC{\alpha}$ accompanied pErk1/2 to the nucleus after freeing it from $PEA-15pS^{104}$ via $PKC{\beta}1$ and then was rapidly ubiquitinated and degraded within the nucleus. Mitogen-activated protein kinase docking motif and kinase activity of $PKC{\alpha}$ were both required for pErk1/2 transport to the nucleus. Repetitive exposure of mouse skin to TPA downregulated $PKC{\alpha}$ expression and increased epidermal and hair follicle cell proliferation. Thus, $PKC{\alpha}$ downregulation is accompanied by in vivo cell proliferation, as evidenced in 7, 12-dimethylbenz(a)anthracene (DMBA)-TPA-mediated carcinogenesis. The ability of TPA to reverse senescence was further demonstrated in old HDF cells using RNA-sequencing analyses in which TPA-induced nuclear $PKC{\alpha}$ degradation freed nuclear pErk1/2 to induce cell proliferation and facilitated the recovery of mitochondrial energy metabolism. Our data indicate that TPA-induced senescence reversal and carcinogenesis promotion share the same molecular pathway. Loss of $PKC{\alpha}$ expression following TPA treatment reduces pErk1/2-activated SP1 biding to the $p21^{WAF1}$ gene promoter, thus preventing senescence onset and overcoming G1/S cell cycle arrest in senescent cells.

• Proceedings of the Ginseng society Conference
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• 1998.06a
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• pp.270-280
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• 1998

Ginseng is one of the most widely used medicinal plants, particularly in East Asian countries. Certain fractions or purified ingredients of ginseng have been shown to exert inhibitory effects on growth of cancer cells in culture or on tumorigenesis in experimental animals. Moreover, a recent epidemiologic study reveals that ginseng intake is associated with a reduced risk for environmentally related cancers such as esophageal, gastric, colorectal, and pulmonary tumors. Heat treatment of Panax ginseng C. A. Meyer at the temperature higher than that applied to the conventional preparation of red ginseng yielded a mixture of saponins with potent antioxidative properties. Thus, the methanol extract of heat-processed ginseng (designated as'NGMe') attenuated lipid peroxidation in rat brain homogenates induced by ferric ion or ferric ion plus ascorbic acid. Furthermore, the extract protected against strand scission in f Xl 74 supercoiled DNA Induced by UV photolysis of H2O2 and was also capable of scavenging superoxide generated in vitro by xanthine/xanthine oxidate or in differentiated human promyelocytic leukemia (HL-60) cells by the tumor promoter,12-0-tetvade- canoylphorbol-13-acetate (TPA). Since tumor promotion is closely linked to oxidative stress, we have determined possible anti-tumor promotional effects of NGMe on two-stage mouse skin tumorigenesis. Topical application of NGMe onto shaven backs of female ICR mice 10 min prior to TPA significantly ameliorated skin papillomagenesi s initiated by 7,12-dimethylbenz (a) anthracene (DMBA).'Likewise, TPA-induced epidermal ornithine decarboxylase activity and elevation of tumor necrosis factor-a were suppressed signifies%fly by NGMe pretreatment. NGMe topically applied onto surface of hamster buccal pouch 10 min before each topical application of DMBA inhibited oral carcinogenesis by 76olo in terms of multiplicity. Taken together, these results suggest that processed Panax ginseng C. A. Meyer has potential cancer chemopreventive activities.

• Journal of Life Science
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• v.27 no.8
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• pp.965-973
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• 2017

Conjugated linoleic acid (CLA) is a group of positional and geometric isomers of linoleic acid with conjugated double bonds at C9,C11 and C10,C12 positions. Of possible CLA isomers, a naturally occurring CLA isomer is c9,t11-CLA which is produced from linoleic acid by linoleate isomerase from various rumen and lactic bacteria, and mushroom mycelia. Meanwhile, synthetically prepared CLA contained an equal amount of c9,t11-CLA and t10,c12-CLA isomers, and other isomers as minor constituents. CLA was firstly mentioned in 1939 during the elaidinization reaction of linoleic acid. Thereafter, CLA was not an attractant to scientists because it was not scientifically interested any more. However, since the anticarcinogenic action was driven from 7,12-dimethylbenz[a]anthracene (DMBA)-induced mouse skin carcinogenesis in 1987, CLA-related researches were drastically elevated, resulting in approximately 6,100 research papers in literature, so far. CLA exhibited the significant biological activities: anticarcinogenic, antidiabetic, antihypertensive, antiatherosclerotic, body-fat reducing, antioxidative, antiinflammatory, testosterone producing and other activities. Interestingly, two major CLA isomers, c9,t11-CLA and t10,c12-CLA, exhibited different biological activities. Meanwhile, t,t-CLA isomers which is minor constituent of chemically synthesized CLA from linoleic acid exhibited more potent anticarcinogenic activity in carcinogen-induced animal models and cancer cell lines than other CLA isomrs. In the present review, the significant biological activities of CLA were discussed along with historical studies of CLA since 1939.

• Current Optics and Photonics
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• v.1 no.1
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• pp.51-59
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• 2017

In addition to its typical use for skin rejuvenation, fractional laser irradiation of early cancerous lesions may reduce the risk of tumor development as a byproduct of wound healing in the stroma after the controlled injury. While fractional ablative lasers are commonly used for cosmetic/aesthetic purposes (e.g., photorejuvenation, hair removal, and scar reduction), we propose a novel use of such laser treatments as a stromal treatment to delay tumorigenesis and suppress carcinogenesis. In this study, we found that non-ablative fractional laser (NAFL) irradiation may have a possible suppressive effect on early tumor growth in syngeneic mouse tumor models. We included two syngeneic mouse tumor models in irradiation groups and control groups. In the irradiation group, a thulium fiber based NAFL at 1927 nm was used to irradiate the skin area including the tumor injection region with 70 mJ/spot, while no laser irradiation was applied to the control group. Numerical simulation with the same experimental condition showed that thermal damage was confined only to the irradiation spots, sparing the adjacent tissue area. The irradiation groups of both tumor models showed smaller tumor volumes than the control group at an early tumor growth stage. We also detected elevated inflammatory cytokine levels a day after the NAFL irradiation. NAFL treatment of the stromal tissue could potentially be an alternative anticancer therapeutic modality for early tumorigenesis in a minimally invasive manner.

• Molecules and Cells
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• v.41 no.2
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• pp.73-82
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• 2018

Cancer preventive activities of green tea and its main constituent, (-)-epigallocatechin gallate (EGCG) have been extensively studied by scientists all over the world. Since 1983, we have studied the cancer chemopreventive effects of EGCG as well as green tea extract and underlying molecular mechanisms. The first part of this review summarizes groundbreaking topics with EGCG and green tea extract: 1) Delayed cancer onset as revealed by a 10-year prospective cohort study, 2) Prevention of colorectal adenoma recurrence by a double-blind randomized clinical phase II trial, 3) Inhibition of metastasis of B16 melanoma cells to the lungs of mice, 4) Increase in the average value of Young's moduli, i.e., cell stiffness, for human lung cancer cell lines and inhibition of cell motility and 5) Synergistic enhancement of anticancer activity against human cancer cell lines with the combination of EGCG and anticancer compounds. In the second part, we became interested in cancer stem cells (CSCs). 1) Cancer stem cells in mouse skin carcinogenesis by way of introduction, after which we discuss two subjects from our review on human CSCs reported by other investigators gathered from a search of PubMed, 2) Expression of stemness markers of human CSCs compared with their parental cells, and 3) EGCG decreases or increases the expression of mRNA and protein in human CSCs. On this point, EGCG inhibited self-renewal and expression of pluripotency-maintaining transcription factors in human CSCs. Human CSCs are thus a target for cancer prevention and treatment with EGCG and green tea catechins.

• The Korean Journal of Pharmacology
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• v.18 no.1
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• pp.65-72
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• 1982

It has been known that retinoids are intrinsically of critical importance for control of premalignant epithelial cell differentiation. In the absence of retinoids, normal cellular differentiation and growth does not occur in epithelia such as those of trachea and bronchi. Furthermore, it was also reported that retinoid deficiency enhanced susceptibility to chemical carcinogenesis in the respiratory system, in the bladder, and in the colon of the experimental animal. In 1974, Bollag examined the effects of synthetic retinoids in prevention of development of cancer and demonstrated synthetic retinoids to have more favorable therapeutic index than retinoic acid for causing regression of skin papilloma in mice. Therefore, it was assumed that this anticarcinogenic effect of vitamin A derivatives could be due to modification of the metabolism of the carcinogenic polycyclic hydrocarbon, which must first be activated to exert their effect. Hill and Shih reported that vitamin A compounds and analogs had inhibitory effect on drug metabolizing enzyme from liver and lung tissue of mouse and hamster. Lucy suggested that the chemoprevention effect of vitamin A derivatives is due to reaction with molecular oxygen, and it is possible that inhibition of hydroxybenzpyrene formation is a result of this property. On the other hand, butylated hydroxytoluene which is a potent antioxidant strongly inhibited the formation of mammary tumor induced by dimethylbenranthracene. Also, it was observed that this antioxidant inhibited cancer induction in rats by N-2-fluo-renylacetamide. The purpose of this experiment was to investigate the effect of vitamin A derivatives such as retinoic acid and retinoid on drug-metabolizing enzyme and to determine whether riboflavin tetrabutylate or vitamin E could prevent of modify any changes induced by vitamin A delivatives in the rats. The results obtained were as followings. 1) Body weight was significantly reduced by retinoic acid, but not by retinoid. 2) Retinoic acid markedly increased liver weight while retincid showed no effect on liver weight. Treatment of riboflavin tetrabutylate did not affect retinoic acid-induced change in both body weight and liver weight. 3) Both retinoic acid and retinoid remarkably decreased the activity of aminopyrine demethylase. Pretreatment of riboflavin tetrabutylate, however, prevented inhibitory effect of retinoic acid on the enzyme activity. 4) No significant effect of vitamin E on aminopyrine demethylase was observed in both groups treated with retinoic acid and retinoid.