Molecular target-based therapy of pancreatic cancer.

Pancreatic cancer is genetically complex, and without effective therapy. Mutations in the Kirsten-ras (K-ras) oncogene occur early and frequently (approximately 90%) during pancreatic cancer development and progression. In this context, K-ras represents a potential molecular target for the therapy of this highly aggressive cancer.

Punica granatum (pomegranate) flower extract possesses potent antioxidant activity and abrogates Fe-NTA induced hepatotoxicity in mice.

Most pomegranate (Punica granatum Linn., Punicaceae) fruit parts are known to possess enormous antioxidant activity. The present study evaluated antioxidant and hepatoprotective activity of pomegranate flowers.

Differential expression of E prostanoid receptors in murine and human non-melanoma skin cancer.

Enhanced prostaglandin production via upregulated cyclooxygenase-2 (COX-2) expression is a likely contributing factor in ultraviolet B (UVB)-induced non-melanoma skin cancer (NMSC), which consists primarily of squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). The four E prostanoid (EP) receptors, designated EP1 through EP4, are known to bind prostaglandin E2 (PGE2), the major prostaglandin present in the skin. We used murine models of UVB-induced SCC and BCC, as well as human NMSC from sun-exposed sites, to investigate the expression of EP receptors during UVB-induced tumorigenesis.

Inhibitory effect of 18beta-glycyrrhetinic acid on 12-O-tetradecanoyl phorbol-13-acetate-induced cutaneous oxidative stress and tumor promotion in mice.

Glycyrrhetinic acid is an aglycone of glycyrrhizic acid, another major active component of licorice roots. Licorice root extract has been used for a long time as a medicine and a natural sweetening additive. In the present study, we found that glycyrrhetinic acid inhibits 12-O-tetradecanoylphorbol-13-acetate (TPA) mediated oxidative stress and tumor promotion in murine skin.

Role of p38 MAPK in UVB-induced inflammatory responses in the skin of SKH-1 hairless mice.

The p38 mitogen-activated protein kinase (MAPK) signaling pathway is activated by numerous inflammatory mediators and environmental stresses. We assessed the effects of ultraviolet B (UVB) on the p38 MAPK pathway and determined whether cyclooxygenase (COX)-2 expression is downstream of this kinase in the skin of UVB-irradiated SKH-1 mice. SKH-1 mice were irradiated with a single dose of UVB (360 mJ per cm2), and activation of the epidermal p38 MAPK pathway was assessed.

Vitamin E inhibits hepatic oxidative stress, toxicity and hyperproliferation in rats treated with the renal carcinogen ferric nitrilotriacetate.

Ferric nitrilotriacetate (Fe-NTA) is a potent renal and hepatic tumor promoter, which acts through a mechanism involving oxidative stress. Fe-NTA when injected intraperitoneally into rats induces hepatic ornithine decarboxylase activity as well as hepatic DNA synthesis. Vitamin E is a well-known, lipid-soluble and chain-breaking antioxidant which protects cell membranes from peroxidative damage.

Mitochondrial damage mediates genotoxicity of arsenic in mammalian cells.

Arsenic is an important environmental carcinogen that affects millions of people worldwide through contaminated water supplies. For decades, arsenic was considered a nongenotoxic carcinogen. Using the highly sensitive A(L) mutation assay, we previously showed that arsenic is, indeed, a potent gene and chromosomal mutagen and that its effects are mediated through the induction of reactive oxygen species.

Two New Compounds from the Galls of Quercus infectoria. with Nitric Oxide and Superoxide Inhibiting Ability.

Two compounds isolated from the ethanol extract of the galls of Quercus infectoria. Olivier exhibited nitric oxide (NO) and superoxide [Formula: see text] inhibiting activity. Their structures were established as ellagic acid-4-O.

Inhibition of smoothened signaling prevents ultraviolet B-induced basal cell carcinomas through regulation of Fas expression and apoptosis.

Abnormal activation of the hedgehog-signaling pathway is the pivotal abnormality driving the growth of basal cell carcinomas (BCCs), the most common type of human cancer. Antagonists of this pathway such as cyclopamine may therefore be useful for treatment of basal cell carcinomas and other hedgehog-driven tumors. We report here that chronic oral administration of cyclopamine dramatically reduces ( approximately 66%) UVB induced basal cell carcinoma formation in Ptch1(+/-) mice.

Elevated polyamines lead to selective induction of apoptosis and inhibition of tumorigenesis by (-)-epigallocatechin-3-gallate (EGCG) in ODC/Ras transgenic mice.

Tea polyphenolic constituents induce apoptosis in cancer cells but not in normal cells. To study the mechanism of this selective effect, we used the ornithine decarboxylase (ODC)/Ras double transgenic mouse model that develops spontaneous skin tumors due to over-expression of ODC and a v-Ha-ras transgene. Administration of the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) in the drinking water significantly decreased both tumor number and total tumor burden compared with untreated ODC/Ras mice without decreasing the elevated polyamine levels present in the ODC/Ras mice.

Ornithine decarboxylase is a target for chemoprevention of basal and squamous cell carcinomas in Ptch1+/- mice.

Solar ultraviolet B (UVB) radiation induces cutaneous ornithine decarboxylase (ODC), the first enzyme in the polyamine-biosynthesis pathway, which drives continued proliferation and clonal expansion of initiated (mutated) cells, leading to tumorigenesis. Therefore ODC is a potentially important target for chemoprevention of basal cell carcinomas (BCCs), the majority of which have mutations in the tumor-suppressor gene known as patched (PTCH). To assess this possibility, we first overexpressed ODC in the skin of Ptch1+/- mice using a keratin 6 (K6) promoter that directs constitutive ODC expression in the outer root sheath of the hair follicle.

Immunoprevention of basal cell carcinomas with recombinant hedgehog-interacting protein.

Basal cell carcinomas (BCCs) are driven by abnormal hedgehog signaling and highly overexpress several hedgehog target genes. We report here our use of one of these target genes, hedgehog-interacting protein (Hip1), as a tumor-associated antigen for immunoprevention of BCCs in Ptch1+/- mice treated with ionizing radiation. Hip1 mRNA is expressed in adult mouse tissues at levels considerably lower than those in BCCs.

Photoprotective effects of sulindac against ultraviolet B-induced phototoxicity in the skin of SKH-1 hairless mice.

Sulindac is a nonsteroidal anti-inflammatory drug with demonstrated potency as a chemopreventive agent in animal models of carcinogenesis and in patients with familial adenomatous polyposis. Because tumor promotion is generally associated with exposure to pro-inflammatory stimuli, it is likely that anti-inflammatory agents may have potent antitumor effects. In human skin, sulindac reduces bradykinin-induced edema.

Antiinflammatory evaluation of alcoholic extract of galls of Quercus infectoria.

Galls of Quercus infectoria Olivier (Fagaceae) possess pleiotropic therapeutic activities, with particular efficacy against inflammatory diseases. The present study was undertaken to evaluate the effect of alcoholic extract of Q. infectoria galls on various in vivo and in vitro experimental models of inflammation.

Low iron diet retards 12-O-tetradecanoyl phorbol-13-acetate-mediated tumor promotion in murine skin.

Recently, we have shown that low iron state reduces benzoyl peroxide-mediated tumor promotion in murine skin. To further test the dependence of iron on skin tumor development, we assessed the effect of a low iron diet on 12- O-tetradecanoyl phorbol-13-acetate (TPA)-mediated tumor promotion in murine skin. Female Swiss albino mice were fed on a low iron diet and initiated with a single dose of 7,12-dimethylbenz[ a]anthracene (DMBA, 40 microg as 150 microl per mouse) and promoted with TPA (2.

Free radical generating agents lead to the rapid progression of benign skin tumors to carcinoma in iron-overloaded mice.

Free radical generating compounds have been shown to enhance the malignant conversion of papillomas to carcinomas in mouse skin, and iron has been shown to participate in free radical generating reactions. In the present study, we investigated whether iron can play a role in the malignant conversion of papillomas to carcinomas. Skin tumors were chemically induced in female Swiss albino mice using a standard two-stage initiation-promotion protocol.

Cyclooxygenases in the skin: pharmacological and toxicological implications.

Cyclooxygenase (COX), a prostaglandin-endoperoxide synthase (PTGS), catalyzes the formation of prostaglandins from arachidonic acid. Prostaglandins are lipid signaling mediators that play a central role in a broad range of diverse physiological and pathophysiological processes, including inflammation, reproduction, nocioception, and gastrointestinal protection. Inhibition of cyclooxygenase activity is the mechanism by which nonsteroidal antiinflammatory drugs (NSAIDS) exert their analgesic, antipyretic, antiinflammatory, and antithrombotic effects.

Roles of catalase and hydrogen peroxide in green tea polyphenol-induced chemopreventive effects.

The green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) possesses promising anticancer potential. Although in vivo studies unveiled the metabolic routes and pharmacokinetics of EGCG and showed no adverse effects, in vitro studies at high concentrations demonstrated oxidative stress. EGCG causes differential oxidative environments in tumor versus normal epithelial cells, but the roles that EGCG, hydrogen peroxide (H2O2), and intracellular catalase play in the epithelial system are largely unknown.

Glyceryl trinitrate, a nitric oxide donor, abrogates ferric nitrilotriacetate-induced oxidative stress and renal damage.

Ferric nitrilotriacetate (Fe-NTA), a common water pollutant and a known renal carcinogen, acts through the generation of oxidative stress and hyperproliferative response. In the present study, we show that the nitric oxide (NO) generated by the administration of glyceryl trinitrate (GTN) affords protection against Fe-NTA-induced oxidative stress and proliferative response. Administration of Fe-NTA resulted in a significant (P<0.

Baculoviral p35 inhibits oxidant-induced activation of mitochondrial apoptotic pathway.

In this study we report that the baculovirus p35 anti-apoptotic protein prevents cell death by quenching free radicals at a very upstream step in the apoptotic pathway. Mitochondria of activated rat peritoneal macrophages as well as Spodoptera frugiperda (Sf9) insect cells, following treatment with oxidants, H(2)O(2)/UVB irradiation, release cytochrome c followed by activation of caspase-3. Transfection of macrophages/Sf9 cells with a construct carrying the p35 gene under the CMV/HSP promoters resulted in p35 expression and consequent arrest of oxidative stress-induced apoptosis.

Green tea polyphenol targets the mitochondria in tumor cells inducing caspase 3-dependent apoptosis.

Induction of apoptosis by green tea polyphenols has been observed in various tumor cell systems, but whether green tea polyphenol-induced apoptosis requires caspase 3 for execution has not been confirmed. We previously reported that green tea polyphenol-induced apoptosis involved Apaf-1 accumulation and caspase 3 activation in the cytosol. In the current study, tumor cells either with deleted caspase 3 gene or expressing wild-type caspase 3 were treated with increasing concentrations of green tea polyphenol(s), followed by morphological analysis and caspase 3 activity assay.

Antioxidants prevent UV-induced apoptosis by inhibiting mitochondrial cytochrome c release and caspase activation in Spodoptera frugiperda (Sf9) cells.

Oxidative stress has been shown to be associated with apoptosis (programmed cell death) in a number of cell systems. We earlier reported in vitro cultured Spodoptera frugiperda (Sf9) cells as a model system to study oxidative stress induced apoptosis (J Biosciences 24 (1999) 13) and the inhibition of UV-induced apoptosis by the baculovirus antiapoptotic p35 protein that acts as a sink to sequester reactive oxygen species (Proc Natl Acad Sci USA 96 (1999) 4838). We now show that UV-induced apoptosis in Sf9 cells, is preceded by the release of mitochondrial cytochrome c into the cytosol and consequent activation of Sf-caspase-1.

Palm oil alleviates 12-O-tetradecanoyl-phorbol-13-acetate-induced tumor promotion response in murine skin.

Palm oil is a rich source of vitamin E, carotenoids, tocotrienols and tocopherols which are natural antioxidants and act as scavengers of oxygen free radicals. 12-O-Tetradecanoyl-phorbol-13-acetate (TPA) is a known oxidant that promotes tumorigenesis in mouse skin through the elaboration of oxidative stress. In this study we therefore assessed the anti-tumor promoting potential of palm oil against TPA-mediated skin tumorigenesis in 7,12-dimethylbenz[a]anthracene-initiated Swiss albino mice.

Oxidative stress and experimental carcinogenesis.

The focus of this review is to provide state-of-the-art knowledge on the involvement of oxygen free radicals (OFR) in carcinogenesis with a particular reference to skin model system as the process of cancer development is best understood in this organ. However, a brief description of the role of OFR in other organs is also provided. The term OFR refers to forms of oxygen exhibiting high reactivity and having at least one unpaired electron.