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Fruits Offer Powerful Protection from Skin Cancer

Contacts:Warren Froelich/AACR215/440-9300/froelich@aacr.org

Aimee Frank/Spectrum Science 202/955-6222/amf@spectrumscience.com

PHOENIX – Fruits contain a number of vitamins and minerals that are used as supplements to treat everyday illnesses. Now, research suggests that common fruit extracts may have significant clinical benefits in decreasing risk for skin cancer. These studies are presented today at the American Association for Cancer Research Second Annual International Conference on Frontiers in Cancer Prevention Research.

“The incidence of skin cancer is rising faster than any other solid tumor in the United States. It is critical that we develop novel approaches to both primary and secondary prevention of what appears to be becoming an epidemic,” said David Alberts, M.D., of the University of Arizona.

“We are pleased to see numerous studies exploring the therapeutic value of topically-applied natural ingredients that people can begin incorporating into everyday life and may enhance the activity of standard sunscreens.”

Pomegranate Fruit Extract is a Novel Agent for Cancer Chemoprevention: Studies in Mouse Skin (Abstract 1547)

The search for novel anti-cancer therapies is ongoing, especially in the area of skin cancer, which is the most frequently diagnosed malignancy in the United States. According to researchers from the University of Wisconsin, one promising agent against skin cancer may have been found in the extract of the pomegranate fruit.

Pomegranate fruit extract (PFE), from the tree Punica granatum, contains several polyphenols and anthocyanidins (pigment that gives certain fruits their dark red colors), the antioxidant activity of which is higher than that of red wine and green tea. In this study, researchers evaluated pomegranate's anti-skin tumor effects by comparing topical application of pomegranate extract on neonatal mice (CD-1) against TPA-induced markers (12-0-tetradecanoylphorbol-13-acetate), a strong promoter of chemically induced skin cancer. Applying pomegranate extract (2 mg/mouse) onto the skin of neonatal mice 30 minutes prior to TPA (3.2 µmole/mouse) application significantly inhibited TPA-mediated increases in skin edema and hyperplasia. TPA is an irritant and inflammatory agent that is widely used as a tumor promoter on the skin of mice.

Researchers also assessed the effect of skin application of pomegranate extract on TPA-induced skin tumor promotion. The animals pretreated with pomegranate extract showed substantially reduced tumor incidence and lower tumor body burden. In the TPA treated group, all mice developed tumors at 16 weeks, whereas only 30 percent of the mice treated with pomegranate extract exhibited tumors at that point.

“For the first time, we have clear evidence that pomegranate extract possesses anti-skin-tumor-promoting effects,” said Dr. Farrukh Afaq, of the University of Wisconsin, and lead investigator of the study.

“With such a variety of pathways inhibited by the topical application of the natural supplement, we are confident of its therapeutic value and hope it will translate to other models.”

According to the researchers, because pomegranate is capable of inhibiting conventional as well as novel biomarkers of TPA-induced tumors, it may possess chemopreventive activity in a wide range of tumor models. To determine the potential value of pomegranate, researchers will pursue an in-depth study to define its active agent(s).

Chemoprevention of Multiple Ultraviolet B-Mediated Damages in SKH-1 Hairless Mouse Skin by Grape Polyphenol Resveratrol: The Underlying Mechanism (Abstract 1489)

Knowing that the greater public will never stay far from the beach, researchers are constantly searching for novel approaches to manage risk factors for skin cancer, including damage from frequent exposure to solar ultraviolet (UV) radiation, particularly its UVB component. In this study, resveratrol, an antioxidant in grapes and red wines, was studied to determine its chemopreventive potential against UVB-mediated skin damage.

As frequent UVB radiation increases skin cancer risk, researchers evaluated the effect of topical application of resveratrol (10 µmole/mouse/0.2 ml acetone) on multiple UVB (seven consecutive exposures in 7 days) exposure-mediated damages in the skin of SKH-1 hairless mice.

Researchers evaluated resveratrol's influence on survivin, which is involved in the control of cell division, and is a structurally unique member of the apoptosis inhibitors protein family. Survivin is overexpressed in most human cancers, but absent in normal adult tissues, and is considered a promising therapeutic target for novel anticancer therapies. Results of the study showed that resveratrol treatment significantly decreased UVB exposure-mediated up-regulation in the mRNA levels and protein expression of survivin.

“We're pleased to see that resveratrol is able to modulate multiple signaling in the cells, which actually protects the skin cells from damages that may lead to the development of cancer,” said Dr. Nihal Ahmad, of the University of Wisconsin, and lead author of the study.

“Further study should continue to support the argument to incorporate this agent into skin care products and regular diets, through the moderate consumption of grapes and red wine.”

Resveratrol significantly inhibited UVB-mediated increases in skin thickness and edema; epidermal cyclooxygenase (COX-2); ornithine decarboxylase (ODC) enzyme and protein levels; and protein levels of proliferating cell nuclear antigen (PCNA), all of which are established markers of tumor promotion. Resveratrol also further stimulated a UVB-mediated increase in p53 protein levels and was found to inhibit UVB exposure-mediated increases in cell cycle promoting signals including the activation of cell division.

Modulation of Ultraviolet Radiation B Induced Wnt-Signaling by Perillyl Alcohol in Human Keratinocytes (Abstract 1385)

Perillyl alcohol (PEOH) is a food additive and a compound found naturally in tart cherries, mint and citrus fruits, such as orange peel. Evidence has shown that this class can inhibit the growth of many cancers and pre-cancerous lesions by helping rid the body of cancer-causing chemicals or by interfering with signals that cause rapid cell division. Researchers in this study determined that the compound maintains its chemopreventive effects against skin cancer.

“Our research has documented that perillyl alcohol is a potent in vivo (living cells) inhibitor of both UVB-induced non-melanoma and melanoma in a transgenic animal model,” said Janine Einspahr, Ph.D., of the Arizona Cancer Center in Tucson, and lead author of the study.

“We are confident that further research will garner results that support these findings in human models. Phase I and Phase II studies of topically-administered perillyl alcohol have been initiated at the Arizona Cancer Center,” she added.

In the study, human keratinocytes (skin cells) were treated for 24 hours with .43 millimolars of PEOH, followed by exposure to 250 millijoules per cm2 of ultraviolet B radiation (UVB). RNA was isolated for analysis immediately following UVB exposure, as well as at half, two, six and 24 hours. As compared to untreated cells, expression of 5,533 genes was notably altered (greater than two fold) with UVB, and 5,837 genes with UVB and PEOH.

Wnt-inhibitory factor-1 (WIF-1) and the Dvl inhibitory protein (IDAX) prevent activation of Wnt responsive genes. UVB alone suppressed WIF-1 expression as much as five fold at two hours, while UVB and PEOH increased expression as much as two and a half fold at the six hour time point. Similarly, UVB alone suppressed IDAX expression as much as three fold at two hours, while UVB and PEOH increased expression as much as nine fold immediately following exposure. The Wnt responsive gene, c-myc, was unchanged with UVB, while UVB and PEOH suppressed expression as much as seven fold at two hours.

The Wnt signaling pathway helps regulate cell structure, movement and growth. Activation of the pathway requires the ligand to bind to a frizzled receptor (the Wnt signal lead receptor). This stimulates the cytoplasmic protein, disheveled (Dvl), one of the multi-module proteins working in the pathway. As a result, accumulated catenins, or protein mutations, situate themselves in the nucleus of the cell. This translocation leads to the transcription of Wnt targeted genes, such as c-myc, causing cancer.

Skin cancer is the most common cancer, with more than 1.3 million new cases expected in 2003. Additionally, the American Cancer Society estimates that in 2003, there will be 54,200 new cases of melanoma, and about 7,600 people will die of this disease.

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Founded in 1907, the American Association for Cancer Research is a professional society of more than 21,000 laboratory, translational, and clinical scientists engaged in cancer research in the United States and in more than 60 other countries. AACR's mission is to accelerate the prevention and cure of cancer through research, education, communication, and advocacy. Its principal activities include the publication of five major peer-reviewed scientific journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. AACR's annual meetings - next year in Orlando, Fla., March 27-31 - attract more than 15,000 participants who share new and significant discoveries in the cancer field. Specialty meetings like this one, held throughout the year, focus on the latest developments in all areas of cancer research.

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