Antioxidants in chemoprevention of skin cancer.
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Administration, Oral↗
Biomedical subjects
H Mukhtar
Publications and source records attributed to H Mukhtar.
Recombinant human tumor necrosis factor alpha does not potentiate cell killing after photodynamic therapy with a silicon phthalocyanine in A431 human epidermoid carcinoma cells.
Photodynamic therapy (PDT) is a novel cancer treatment utilizing a photosensitizer, visible light and oxygen. PDT with the silicon phthalocyanine Pc 4, a new photosensitizer, is highly effective in cancer cell destruction and tumor ablation. The mechanisms underlying cancer cell killing by PDT are not fully understood. Tumor necrosis factor alpha (TNF) is a multifunctional cytokine that has been implicated in photocytotoxicity. We asked whether recombinant human TNF (rhTNF) affects Pc 4-PDT cytotoxicity in A431 human epidermoid carcinoma cells. Co-treatment of A431 cells with various doses of Pc 4-PDT and a sub-lethal rhTNF dose led to a sub-additive reduction in cell survival. In addition, in the presence of Pc 4-PDT or rhTNF, caspase-3 activity and apoptosis were induced. The combined treatment, however, did not potentiate either caspase-3 activity or apoptosis. Similar to previous findings we observed that Pc 4-PDT initiated a time-dependent extracellular TNF accumulation. The data suggest that: a) PDT and rhTNF induce cancer cell killing through different mechanisms; and b) Pc 4-PDT-induced TNF production is a stress response that may not directly affect photocytotoxicity.
Apoptosis↗
Resveratrol causes WAF-1/p21-mediated G(1)-phase arrest of cell cycle and induction of apoptosis in human epidermoid carcinoma A431 cells.
Resveratrol (trans-3,4',5,-trihydroxystilbene), a phytoalexin found in grapes, nuts, fruits, and red wine, is a potent antioxidant with cancer-preventive properties. The mechanism by which resveratrol imparts cancer chemopreventive effects is not clearly defined. Here, we demonstrate that resveratrol, via modulations in cyclin-dependent kinase (cdk) inhibitor-cyclin-cdk machinery, results in a G(1)-phase arrest of the cell cycle followed by apoptosis of human epidermoid carcinoma (A431) cells. Resveratrol treatment (1-50 microM for 24 h) of A431 cells resulted in a dose-dependent (a) inhibition of cell growth as shown by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, (b) G(1)-phase arrest of the cell cycle as shown by DNA cell cycle analysis, and (c) induction of apoptosis as assessed by ELISA. The immunoblot analysis revealed that resveratrol treatment causes a dose- and time-dependent (a) induction of WAF1/p21; (b) decrease in the protein expressions of cyclin D1, cyclin D2, and cyclin E; and (c) decrease in the protein expressions of cdk2, cdk4, and cdk6. Resveratrol treatment was also found to result in a dose- and time-dependent decrease in kinase activities associated with all of the cdks examined. Taken together, our study suggests that resveratrol treatment of the cells causes an induction of WAF1/p21 that inhibits cyclin D1/D2-cdk6, cyclin D1/D2-cdk4, and cyclin E-cdk2 complexes, thereby imposing an artificial checkpoint at the G(1)-->S transition of the cell cycle. This series of events results in a G(1)-phase arrest of the cell cycle, which is an irreversible process that ultimately results in the apoptotic death of cancer cells. To our knowledge, this is the first systematic study showing the involvement of each component of cdk inhibitor-cyclin-cdk machinery during cell cycle arrest and apoptosis of cancer cells by resveratrol.
Antineoplastic Agents, Phytogenic↗
Green tea polyphenol (-)-epigallocatechin-3-gallate treatment to mouse skin prevents UVB-induced infiltration of leukocytes, depletion of antigen-presenting cells, and oxidative stress.
Ultraviolet (UV) radiation-induced infiltrating leukocytes, depletion of antigen-presenting cells, and oxidative stress in the skin play an important role in the induction of immune suppression and photocarcinogenesis. Earlier we have shown that topical application of polyphenols from green tea or its major chemopreventive constituent (-)-epigallocatechin-3-gallate (EGCG) prevents UV-B-induced immunosuppression in mice. To define the mechanism of prevention, we found that topical application of EGCG (3 mg/mouse/3 cm(2) of skin area) to C3H/HeN mice before a single dose of UV-B (90 mJ/cm(2)) exposure inhibited UV-B-induced infiltration of leukocytes, specifically the CD11b+ cell type, and myeloperoxidase activity, a marker of tissue infiltration of leukocytes. EGCG treatment was also found to prevent UV-B-induced depletion in the number of antigen-presenting cells when immunohistochemically detected as class II MHC+ Ia+ cells. UV-B-induced infiltrating cell production of H2O2 and nitric oxide (NO) was determined as a marker of oxidative stress. We found that pretreatment of EGCG decreased the number of UV-B-induced increases in H2O2-producing cells and inducible nitric oxide synthase-expressing cells and the production of H2O2 and NO in both epidermis and dermis at a UV-B-irradiated site. Together, these data suggest that prevention of UV-B-induced infiltrating leukocytes, antigen-presenting cells, and oxidative stress by EGCG treatment of mouse skin may be associated with the prevention of UV-B-induced immunosuppression and photocarcinogenesis.
Animals↗
Up-regulation of clusterin during phthalocyanine 4 photodynamic therapy-mediated apoptosis of tumor cells and ablation of mouse skin tumors.
Photodynamic therapy (PDT) using the silicon phthalocyanine photo-sensitizer Pc 4 is an oxidative stress associated with the induction of apoptosis in many cancer cells in vitro and in vivo. The mechanisms of PDT-induced tumor cell killing leading to apoptosis are incompletely understood. Clusterin, a widely expressed glycoprotein, is induced in tissues regressing as a consequence of oxidative stress-mediated cell death. Treatment of apoptosis-sensitive human epidermoid carcinoma cells (A431) with PDT resulted in significant up-regulation of clusterin with a maximum at 12 h after treatment, whereas clusterin levels in Pc 4-PDT-treated, apoptosis-resistant, radiation-induced fibrosarcoma (RIF-1) cells remained unchanged. The i.v. administration of Pc 4 to mice bearing chemically or UVB radiation-induced skin papillomas, followed by light application, led to increased clusterin protein expression, peaking 24 h after the treatment, when tumor regression was apparently visible. These data, for the first time, demonstrate the involvement of clusterin in PDT-mediated cell death and during tumor regression. This may have relevance in improving the efficacy of PDT using pharmacological inducers of clusterin.
Animals↗
Mechanism of ultraviolet B-induced cell cycle arrest in G2/M phase in immortalized skin keratinocytes with defective p53.
The ultraviolet B (UVB) portion (280-320 nm) of solar radiation is considered to be a major etiologic factor in human skin cancer and is a known cause of extensive DNA damage. In this study, we observed that UVB exposure of immortalized epidermal keratinocytes (HaCat cells) harboring mutant p53 leads to G(2)/M cell cycle arrest in both asynchronously growing and synchronized cells in a dose dependent manner. Following UVB exposure (200 mJ/cm(2)), we observed a threefold increase in G(2)/M population at 6 h, which increased to sixfold. The observed G(2)/M arrest was associated with an increase in cyclin B level whereas cdc2 protein remained unchanged. However, we observed an accumulation of tyrosine 15 hyperphosphorylated cyclin B-cdc2 complex. In addition, we observed an increase in chk1 kinase and a decrease in cdc25C protein levels. Chk1 phosphorylates cdc25C on serine 216 and inactivates it whereas cdc25C dephosphorylates tyrosine 15 phosphate of cdc2 and activates the cdc2-cyclin B complex. Therefore, the increase in chk1 and the decrease in cdc25C both participate in inhibiting the G2/M transition. Our data identifies two upstream targets leading to inhibition of cyclin B-cdc2 complexes, which explain the inhibition in cyclin B-associated cdc2 kinase following UVB exposure. The inactive phosphorylated cdc2-cyclin B complex remains sequestered in cytoplasm and may migrate to the nucleus following activation. Our data also indicate that UVB exerts unique effects in different types of skin keratinocytes having nonfunctional or mutant p53.
CDC2 Protein Kinase↗
Chemoprevention of prostate carcinogenesis by alpha-difluoromethylornithine in TRAMP mice.
Development of effective chemopreventive agents for human consumption requires conclusive evidence of their efficacy in animal models that have relevance to human diseases. Transgenic adenocarcinoma mouse prostate (TRAMP) is an excellent model of prostate cancer that mimics progressive forms of human disease inasmuch as 100% of males develop histological PIN by 8-12 weeks of age that progress to adenocarcinoma with distant site metastases by 24-28 weeks of age. In these animals, ornithine decarboxylase (ODC) activity (>3-fold) as well as protein expression (>4-fold) was found to be markedly higher in the dorsolateral prostate as compared with the nontransgenic littermates, suggesting their suitability to determine the chemopreventive effect of alpha-difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor of ODC, against prostate cancer. Using male TRAMP mice, we studied the effect of oral consumption of DFMO on development of prostate carcinogenesis and surrogate end point biomarkers related to prostate cancer progression. In two independent experiments, each consisting of 8 animals on test, the cumulative incidence of prostatic cancer development at 28 weeks of age in 16 untreated TRAMP mice was 100% (16 of 16), whereas 94% (15 of 16) and 69% (11 of 16) of the animals exhibited distant site metastases to lymph nodes and lungs, respectively. Oral consumption of 1% DFMO (w/v) in the drinking water to TRAMP mice from 8 to 28 weeks of age resulted in a significant decrease in (a) weight (59%) and volume (66%) of prostate, (b) genitourinary weight (63%), and (c) ODC enzyme activity (52%) in the dorsolateral prostate. Importantly, in none of the DFMO-fed TRAMP mice were any distant metastases to lymph node and lungs observed. Furthermore, DFMO treatment resulted in the marked reduction in the protein expression of proliferation cell nuclear antigen, ODC, and probasin in the dorsolateral prostate. The protein expression of antimetastases markers, i.e., E-cadherin and alpha- and beta-catenin, was found to be restored in DFMO-fed animals as compared with the non-DFMO-fed mice. These chemopreventive effects of DFMO were further confirmed by immunohistochemical analysis of the dorsolateral prostate. Histological analysis of the dorsolateral prostate of DFMO-fed animals displayed marginal epithelial stratification, a small number of cribriform structures, elongated hyperchromatic epithelial nuclei, and a significant increase in apoptotic index. Non-DFMO-fed animals, on the other hand, displayed extensive epithelial stratification with profound cribriform structures accompanied with marked thickening, remodeling, and hypercellularity of the fibromuscular stroma. In nontransgenic littermates fed with DFMO, no significant alterations in the above parameters were evident. These data demonstrate that ODC represents a promising and rational target for chemoprevention of human prostate cancer and that TRAMP mice are excellent models for screening of novel drugs and chemopreventive regimens for potential human use.
Adenocarcinoma↗
Cell cycle dysregulation by green tea polyphenol epigallocatechin-3-gallate.
Epidemiological, in vitro cell culture, and in vivo animal studies have shown that green tea or its constituent polyphenols, particularly its major polyphenol epigallocatechin-3-gallate (EGCG) may protect against many cancer types. In earlier studies, we showed that green tea polyphenol EGCG causes a G0/G1-phase cell cycle arrest and apoptosis of human epidermoid carcinoma (A431) cells. We also demonstrated that these effects of EGCG may be mediated through the inhibition of nuclear factor kappa B that has been associated with cell cycle regulation and cancer. In this study, employing A431 cells, we provide evidence for the involvement of cyclin kinase inhibitor (cki)-cyclin-cyclin-dependent kinase (cdk) machinery during cell cycle deregulation by EGCG. As shown by immunoblot analysis, EGCG treatment of the cells resulted in significant dose- and time-dependent (i) upregulation of the protein expression of WAF1/p21, KIP1/p27, p16 and p18, (ii) downmodulation of the protein expression of cyclin D1, cdk4 and cdk6, but not of cyclin E and cdk2, (iii) inhibition of the kinase activities associated with cyclin E, cyclin D1, cdk2, cdk4 and cdk6. Taken together, our study suggests that EGCG causes an induction of G1-phase ckis, which inhibit the cyclin-cdk complexes operative in G0/G1 phase of the cell cycle thereby causing a G0/G1-phase arrest of the cell cycle, which is an irreversible process ultimately resulting in an apoptotic cell death. We suggest that the naturally occurring agents such as green tea polyphenols which may inhibit cell cycle progression could be developed as potent anticancer agents for the management of cancer.
Apoptosis↗
Involvement of caspase-3 in epigallocatechin-3-gallate-mediated apoptosis of human chondrosarcoma cells.
Green tea polyphenol-(-)epigallocatechin-3-gallate (EGCG)-is a potent chemopreventive agent in many test systems and has been shown to inhibit tumor promotion and induce apoptosis. In this study we describe a novel observation that EGCG displayed strong inhibitory effects on the proliferation and viability of HTB-94 human chondrosarcoma cells in a dose-dependent manner and induced apoptosis. Investigation of the mechanism of EGCG-induced apoptosis revealed that treatment with EGCG resulted in DNA fragmentation, induction of caspase-3/CPP32 activity, and cleavage of the death substrate poly(ADP-ribose)polymerase (PARP). Pretreatment of cells with a synthetic pan-caspase inhibitor (Z-VAD-FMK) and a caspase-3-specific inhibitor (DEVD-CHO) prevented EGCG-induced PARP cleavage. The induction of apoptosis by EGCG via activation of caspase-3/CPP32-like proteases may provide a mechanistic explanation for its antitumor effects.
Antineoplastic Agents↗
Green tea polyphenol epigallocatechin-3-gallate differentially modulates nuclear factor kappaB in cancer cells versus normal cells.
Green tea has shown remarkable anti-inflammatory and cancer chemopreventive effects in many animal tumor bioassays, cell culture systems, and epidemiological studies. Many of these biological effects of green tea are mediated by epigallocatechin 3-gallate (EGCG), the major polyphenol present therein. We have earlier shown that EGCG treatment results in apoptosis of several cancer cells, but not of normal cells (J. Natl. Cancer Inst. 89, 1881-1886 (1997)). The mechanism of this differential response of EGCG is not known. In this study, we investigated the involvement of NF-kappaB during these differential responses of EGCG. EGCG treatment resulted in a dose-dependent (i) inhibition of cell growth, (ii) G0/G1-phase arrest of the cell cycle, and (iii) induction of apoptosis in human epidermoid carcinoma (A431) cells, but not in normal human epidermal keratinocytes (NHEK). Electromobility shift assay revealed that EGCG (10-80 microM) treatment results in lowering of NF-kappaB levels in both the cytoplasm and nucleus in a dose-dependent manner in both A431 cells and NHEK, albeit at different concentrations. EGCG treatment was found to result in a dose-based differential inhibition of TNF-alpha- and LPS-mediated activation of NF-kappaB in these cells. The inhibition of NF-kappaB constitutive expression and activation in NHEK was observed only at high concentrations. The immunoblot analysis also demonstrated a similar pattern of inhibition of the constitutive expression as well as activation of NF-kappaB/p65 nuclear protein. This inhibition of TNF-alpha-caused NF-kappaB activation was mediated via the phosphorylative degradation of its inhibitory protein IkappaBalpha. Taken together, EGCG was found to impart differential dose-based NF-kappaB inhibitory response in cancer cells vs normal cells; i.e., EGCG-mediated inhibition of NF-kappaB constitutive expression and activation was found to occur at much higher dose of EGCG in NHEK as compared to A431 cells. This study suggests that EGCG-caused cell cycle deregulation and apoptosis of cancer cells may be mediated through NF-kappaB inhibition.
Apoptosis↗
Growth inhibition, cell-cycle dysregulation, and induction of apoptosis by green tea constituent (-)-epigallocatechin-3-gallate in androgen-sensitive and androgen-insensitive human prostate carcinoma cells.
Prostate cancer (PCA) is the most prevalent cancer diagnosed and the second leading cause of cancer-related deaths among men in the United States. Descriptive epidemiological data suggest that androgens and environmental exposures play a key role in prostatic carcinogenesis. Since androgen action is intimately associated with proliferation and differentiation, at the time of clinical diagnosis in humans most PCA represent themselves as a mixture of androgen-sensitive and androgen-insensitive cells. Androgen-sensitive cells undergo rapid apoptosis upon androgen withdrawal. On the other hand, the androgen-insensitive cells do not undergo apoptosis upon androgen blocking, but maintain the molecular machinery of apoptosis. Thus, agents capable of inhibiting growth and/or inducing apoptosis in both androgen-sensitive and androgen-insensitive cells will be useful for the management of PCA. In the present study, we show that (-)-epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent present in green tea, imparts antiproliferative effects against both androgen-sensitive and androgen-insensitive human PCA cells, and this effect is mediated by deregulation in cell cycle and induction of apoptosis. EGCG treatment was found to result in a dose-dependent inhibition of cell growth in both androgen-insensitive DU145 and androgen-sensitive LNCaP cells. In both the cell types, EGCG treatment also resulted in a dose-dependent G(0)/G(1)-phase arrest of the cell cycle as observed by DNA cell-cycle analysis. As evident by DNA ladder assay, confocal microscopy, and flow cytometry, the treatment of both DU145 and LNCaP cells with EGCG resulted in a dose-dependent apoptosis. Western blot analysis revealed that EGCG treatment resulted in (i) a dose-dependent increase of p53 in LNCaP cells (carrying wild-type p53), but not in DU145 cells (carrying mutant p53), and (ii) induction of cyclin kinase inhibitor WAF1/p21 in both cell types. These results suggest that EGCG negatively modulates PCA cell growth, by affecting mitogenesis as well as inducing apoptosis, in cell-type-specific manner which may be mediated by WAF1/p21-caused G(0)/G(1)-phase cell-cycle arrest, irrespective of the androgen association or p53 status of the cells.
Androgens↗
Green tea and skin.
OBJECTIVE: To discuss the current knowledge of polyphenolic compounds present in green tea as anti-inflammatory, antioxidant, and anticarcinogenic in skin. DATA SOURCES: References identified from bibliographies of pertinent articles, including our work in related fields. STUDY SELECTION AND DATA EXTRACTION: Articles were selected based on the use of green tea or its polyphenolic constituents for prevention against inflammation and cancer in the skin. Also discussed is the possible use of green tea to treat various inflammatory dermatoses. DATA SYNTHESIS: The polyphenolic compounds from green tea were tested against chemical carcinogenesis and photocarcinogenesis in murine skin. These green tea polyphenols were found to afford protection against chemical carcinogenesis as well as photocarcinogenesis in mouse skin. A few experimental studies were conducted in human skin in our laboratory. Analysis of published studies demonstrates that green tea polyphenols have anti-inflammatory and anticarcinogenic properties. These effects appear to correlate with antioxidant properties of green tea polyphenols. CONCLUSIONS: The outcome of the several experimental studies suggests that green tea possess anti-inflammatory and anticarcinogenic potential, which can be exploited against a variety of skin disorders. Although more clinical studies are needed, supplementation of skin care products with green tea may have a profound impact on various skin disorders in the years to come. Arch Dermatol. 2000;136:989-994
Administration, Oral↗
Over-expression of cyclooxygenase-2 in human prostate adenocarcinoma.
Aberrant or increased expression of cyclooxygenase (COX)-2 has been implicated in the pathogenesis of many diseases including carcinogenesis. COX-2 has been shown to be over-expressed in some human cancers. Employing semi-quantitative reverse transcription-PCR, immunoblotting, and immunohistochemistry we assessed COX-2 expression in samples of pair-matched benign and cancer tissue obtained from the same prostate cancer patient. Mean levels of COX-2 mRNA were 3.4-fold higher in prostate cancer tissue (n = 12) compared with the paired benign tissue. The immunoblot analysis demonstrated that as compared to benign tissue COX-2 protein was over-expressed in 10 of 12 samples examined. Immunohistochemical analysis also verified COX-2 over-expression in cancer than in benign tissue. To our knowledge, this is the first in vivo study showing an over-expression of COX-2 in prostate cancer. These data suggest that COX-2 inhibitors may be useful for prevention or therapy of prostate cancer in humans.
Adenocarcinoma↗
Mechanism of photodynamic therapy-induced cell death.
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Animals↗
Photodynamic therapy in dermatology.
UNLABELLED: The combination of light and chemicals to treat skin diseases is widely practiced in dermatology. Within this broad use of light and drugs, in recent years the concept of photodynamic therapy (PDT) has emerged. PDT is a promising modality for the management of various tumors and nonmalignant diseases, based on the combination of a photosensitizer that is selectively localized in the target tissue and illumination of the lesion with visible light, resulting in photodamage and subsequent cell death. Moreover, the fluorescence of photosensitizing compounds is also utilized as a helpful diagnostic tool for the detection of neoplastic tissue. Intensive basic and clinical research culminated in the worldwide approval of PDT for bladder, esophageal, and lung cancer. The expanding use of this relatively new therapeutic modality in dermatology at many centers around the world has revealed its efficacy for the treatment of cutaneous precancer and cancer, as well as selected benign skin disorders. The following article summarizes the main principles of PDT considering the most recent developments and provides a comprehensive synopsis of the present status of the use of PDT in dermatology. (J Am Acad Dermatol 2000;42:389-413.) LEARNING OBJECTIVE: At the conclusion of this learning activity, participants should be able to describe the basic concepts of PDT, including fundamental knowledge of the most relevant photosensitizers, the light sources, the mechanisms involved in PDT-mediated cell destruction, as well as the indications and limitations of photodynamic treatment of skin diseases.
Dermatology↗
Involvement of Fas (APO-1/CD-95) during photodynamic-therapy-mediated apoptosis in human epidermoid carcinoma A431 cells.
Photodynamic therapy is a promising treatment modality for a variety of cutaneous neoplasms and other skin disorders. Studies suggest an involvement of multiple pathways during photodynamic-therapy-mediated cell death. A complete knowledge of the mechanisms involved in photodynamic therapy may lead to an improvement in its therapeutic efficacy. In vitro as well as in vivo studies have shown the involvement of apoptosis during photodynamic- therapy-mediated cell death. The pathways by which photodynamic therapy causes this are not fully understood. In this study, employing human epidermoid carcinoma (A431) cells and silicon phthalocyanine 4 photodynamic therapy, we show that the cell surface death receptor Fas (also known as APO-1 or CD-95) pathway is an important contributor to photodynamic-therapy-mediated apoptosis. Employ- ing flow cytometric analysis and confocal microscopy we first established that silicon phthalocyanine 4 photodynamic therapy results in a significant induction of apoptosis in A431 cells. Immunoblot analysis revealed a significant time-dependent increase in the protein expression of Fas at 5, 15, 30, and 60 min post-photodynamic therapy followed by a decrease at later time-points (2 and 3 h post-photodynamic therapy). A Fas enzyme-linked immunosorbent assay demonstrated an increase in this protein in cell culture medium starting at 1 h post-photodynamic therapy and showing a time-dependent response up to 3 h following therapy, suggesting a diffusion of soluble Fas from cells into the medium from 1 h after photodynamic therapy. Silicon phthalocyanine 4 photodynamic therapy also resulted in a time-dependent increase in (i) the multimerization of Fas protein, (ii) the protein expression of Fas ligand, (iii) FADD, an adapter molecule for Fas, and (iv) the binding of FADD with Fas. Silicon phthalocyanine 4 photodynamic therapy also caused a significant activation of FLICE, as evident from the appearance of cleaved products of pro-caspase 8. Further, a pretreatment of cells with rhFas:Fc fusion protein or general caspase inhibitor Z-VAD-FMK followed by silicon phthalocyanine 4 photodynamic therapy resulted in a significantly enhanced cell survival. Taken together, our data, for the first time, delineate an involvement of the Fas pathway as an important contributor to photodynamic-therapy-mediated apoptosis of cancer cells. These observations may be important for improving the efficacy of photodynamic therapy for the treatment of skin cancer and possibly other skin disorders. J Invest Dermatol 115:1041-1046 2000
Apoptosis↗
Ultraviolet-B exposure of human skin induces cytochromes P450 1A1 and 1B1.
The cytochromes P450 belong to a multigene superfamily and are responsible for the metabolic activation of both xenobiotics and endobiotics. The expression of cytochrome P450 genes in target cells is an important determinant of human susceptibility to cancers and other chemically initiated diseases. In this study using immunohistochemistry, reverse transcription polymerase chain reaction, and western blot analysis, we investigated the cellular distribution and localization of cytochrome P450 1A1 and cytochrome P450 1B1 in human skin, and their induction by ultraviolet-B. Through the use of immunohistochemistry, cytochrome P450 1A1 was found to be primarily localized in the basal cell layer of the epidermis in non-ultraviolet-B exposed skin, whereas cytochrome P450 1B1 was localized in the epidermal cells other than the basal cell layer. Thus, localizations of cytochrome P450 1A1 and cytochrome P450 1B1 in human skin are different and may be related to keratinocyte differentiation. Ultraviolet-B exposure to solar-ultraviolet-protected skin (buttock site) resulted in an ultraviolet-B dose-dependent (0-4 minimal erythema doses) and time-dependent (0-48 h) induction of both cytochrome P450 1A1 and cytochrome P450 1B1 in the epidermis. Reverse transcription polymerase chain reaction and western blot analyses revealed that exposure of human skin to ultraviolet-B (4 minimal erythema doses) resulted in enhanced expression of mRNA and protein of both cytochrome P450 1A1 and cytochrome P450 1B1 in the epidermis. Ultraviolet-B induction of both cytochrome P450 1A1 and cytochrome P450 1B1 in human skin will probably result in enhanced bioactivation of polycyclic aromatic hydrocarbons and other environmental pollutants to which humans are exposed, which in turn could make the human skin more susceptible to ultraviolet-B-induced skin cancers or allergic and irritant contact dermatitis.
Adult↗
Tea polyphenols: prevention of cancer and optimizing health.
The tea plant Camellia sinesis is cultivated in >30 countries. Epidemiologic observations and laboratory studies have indicated that polyphenolic compounds present in tea may reduce the risk of a variety of illnesses, including cancer and coronary heart disease. Most studies involved green tea, however; only a few evaluated black tea. Results from studies in rats, mice, and hamsters showed that tea consumption protects against lung, forestomach, esophagus, duodenum, pancreas, liver, breast, colon, and skin cancers induced by chemical carcinogens. Other studies showed the preventive effect of green tea consumption against atherosclerosis and coronary heart disease, high blood cholesterol concentrations, and high blood pressure. Because the epidemiologic studies and research findings in laboratory animals have shown the chemopreventive potential of tea polyphenols in cancer, the usefulness of tea polyphenols for humans should be evaluated in clinical trials. One such phase 1 clinical trial is currently under way at the MD Anderson Cancer Center in collaboration with Memorial Sloan-Kettering Cancer Center. This study will examine the safety and possible efficacy of consuming the equivalent of > or =10 cups (> or =2.4 L) of green tea per day. The usefulness of tea polyphenols may be extended by combining them with other consumer products such as food items and vitamin supplements. This "designer-item" approach may be useful for human populations, but it requires further study.
Animals↗