Our laboratory has used a rodent model of human esophageal squamous cell carcinoma to identify putative chemopreventive agents for this disease and to determine their mechanisms of action. In the present study, we treated F344 rats with the esophageal carcinogen, N-nitrosomethylbenzylamine (NMBA), thrice per week for 5 weeks. Beginning 1 week later, they were fed a synthetic diet containing 5% black raspberries (BRB) for the duration of the bioassay (25 weeks). Rats were sacrificed at weeks 9, 15, and 25. Esophageal tissues were collected, and tumor data were recorded. The expression and enzymatic activities of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) as well as the expression of c-Jun in the esophagi, were evaluated to investigate the mechanism(s) by which black raspberries modulate tumorigenesis. At week 25, BRB inhibited tumor multiplicity, the standard end point in this tumor model, from 3.78 F 0.41 tumors per rat in NMBAtreated animals to 2.23 F 0.21 tumors per rat in animals treated with NMBA plus BRB (P < 0.005). BRB reduced mRNA and protein expression levels of COX-2, iNOS, and c-Jun as well as the level of prostaglandin E 2 in preneoplastic lesions of the esophagus at week 25. The berries inhibited mRNA expression of iNOS and c-Jun, but not COX-2, in papillomatous lesions of the esophagus. Prostaglandin E 2 and total nitrite levels were also decreased by BRB in papillomas. These results suggest a novel tumor suppressive role of BRB through inhibition of COX-2, iNOS, and c-Jun.

Angiogenesis, the formation of new blood vessels, is critical to tumor growth and metastasis. Vascular endothelial growth factor (VEGF), an important angiogenic activator, is essential for angiogenesis. Our laboratory has used a rodent model of human esophageal squamous cell carcinoma (ESCC) to identify putative chemopreventive agents for this disease and determine their mechanisms of action. We reported that dietary black raspberry powder (BRB) inhibits N-nitrosomethylbenzylamine (NMBA)-induced tumor development in the rat esophagus by inhibiting the formation of DNA adducts and reducing the proliferation rate of preneoplastic cells. On a molecular level, BRB downregulates the expression of c-Jun, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). In this study we analyzed the effect of BRB on angiogenesis. VEGF expression was determined by real-time RT-PCR and immunohistochemical analysis of microvessel density (MVD). BRB significantly suppressed VEGF-C expression from a 2.38 (+/- 0.34)-fold increase in animals treated with NMBA alone to a 1.08 (+/- 0.22)-fold increase in animals treated with NMBA plus BRB (P < 0.005). The MVD of esophagus was decreased from 53.7 +/- 5.6 vessels/cm in animals treated with NMBA alone to 22.6 +/- 2.6 vessels/cm in animals treated with NMBA plus BRB (P < 0.0001). Our data also suggest that downregulation of VEGF is correlated with suppression of COX-2 (r2 = 0.86, P < 0.001) and iNOS (r2 = 0.81, P < 0.005). As high vascularity is a risk factor for metastasis and tumor recurrence, BRB may have cancer therapeutic effects in human esophageal cancer.

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Chronic exposure of the skin to ultraviolet B (UVB) radiation induces oxidative stress, which plays a crucial role in the induction of skin cancer. In this study, the effect of dietary feeding and topical application of brown algae polyphenols on UVB radiation-induced skin carcinogenesis in SKH-1 mice was investigated. SKH-1 hairless mice were randomly divided into 9 groups, including control, UVB control and treatment groups. They were treated orally (0.1% and 0.5% with AIN-76 diet, w/w) and topically (3 and 6 mg/0.2 ml of vehicle) with brown algae polyphenols and irradiated with UVB for 26 weeks. Dietary feeding (0.1% and 0.5%) of brown algae polyphenols significantly reduced tumor multiplicity (45% and 56%) and tumor volume (54% and 65%), and topical administration (3 and 6 mg) significantly decreased tumor multiplicity (60% and 46%) and tumor volume (66% and 57%), respectively, per tumor-bearing mouse. Dietary feeding and topical administration of the polyphenols also inhibited tumor incidence by 6% and 21%, respectively, but the results were not significant. Dietary and topical administration of the polyphenols markedly inhibited cyclooxygenase-2 activity and cell proliferation. These observations show that brown algae polyphenols have an antiphotocarcinogenic effect which may be associated with the prevention of UVB-induced oxidative stress, inflammation, and cell proliferation in the skin. ' 2006 Wiley-Liss, Inc.

Armeniacae semen is the seed of the apricot (Prunus armeniaca L. var. ansu MAXIM.), which belongs to the Rosaceae family. It is a traditional drug with many benefits, including the provision of antipyretic, antitussive, anticancer, and thirst-quenching effects. In traditional Oriental medicine, it is used to treat various diseases, including asthma, bronchitis, emphysema, constipation, nausea, leprosy, and leucoderma. 1)Amygdalin, also known as vitamin B17 or laetrile, 2) is a major component of armeniacae semen, and is easily isolated from the stones of rosaceous fruits, such as apricots, almonds, peaches, cherries, and plums. Although it was advocated as a new cancer cure or preventative and examined clinically in the late 1970s and early 1980s, it was not approved by the Food and Drug Administration for cancer treatment due to insufficient clinical evidence of its efficacy and potential toxicity.3) Despite the failure of clinical tests to demonstrate the anticancer effects of amygdalin in the U.S.A. and in Europe, amygdalin continues to be manufactured and administered as an anticancer therapy in northern Europe and Mexico, and few studies have examined other pharmacological activities of amygdalin. Recently, Chang et al. reported that armeniacae semen extract exerted anti-inflammatory and antinociceptive effects by showing the in vitro suppression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression in mouse BV2 microglial cells. 1,4,5) In the present study, formalin-induced behavior was chosen as a model of acute inflammatory pain to evaluate the antinociceptive activity of amygdalin. The rat formalin test has been widely used for analyzing acute nociceptive pain induced by the subcutaneous administration of formalin and continuous tonic pain generated by tissue injury and inflammation in rodents.6,7) In the rat formalin test, formalininduced behaviors, such as licking, biting or shaking the injected paw, are expressed in two clear-cut phases in the 1-h period following formalin injection. The first phase starts immediately after formalin injection and lasts 3-5 min. This is predominantly mediated by c-fiber activation due to the peripheral stimulation of formalin 8,9) and reflects an acute pain state. The second phase starts 15-20 min after formalin injection and lasts 20-60 min, depending on the formalin concentration injected. This pain response is attributed to ongoing afferent input from the peripheral site, which leads to the development of spinal cord hyperexcitability. 10)The expression of an immediate-early gene, c-Fos in the spinal cord dorsal horn, is a marker of the neuronal activity that can be induced by noxious stimuli.11-15) Therefore, it allows quantification of the effects of antinociceptive treatments and the identification their neuroanatomical localization.13,16) Intraplantar formalin injection evokes c-Fos protein expression, principally in superficial (I-II) and deep (III-IV) dorsal horn laminae.16-18) Therefore, we used c-Fos protein expression in the spi...

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