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DERT Papers of the Month

By Jerry Phelps
May 2007

Birch-bark Extract, Betulinic Acid, Inhibits Prostate Cancer Growth

Betulinic acid is an oxidation product of betulin, a traditional medicine product of the triterpene family derived from birch tree bark. Previous research characterized it as an effective inhibitor of human melanoma tumor growth through the induction of apoptosis. Other triterpenoid compounds have the same anti-carcinogenic and anti-inflammatory effects and are currently being studied in clinical trials for their potential use in treating leukemia.

A group of NIEHS-supported researchers reports that betulinic acid might also be an effective treatment for prostate cancer. In a series of experiments using prostate cancer cell cultures and an animal model of prostate cancer, betulinic acid treatment decreased the growth of the cancer cells. The compound induced proteosome-dependent degradation of the specificity protein transcription factors Sp1, Sp3 and Sp4 in the prostate cancer cells. These factors are over-expressed in many tumor types.

These results indicate the anti-tumor effects of betulinic acid are associated with specific degradation of specificity protein transcription factors resulting in the inhibition of blood vessel formation and the activation of pro-apoptotic responses in tumors, but not in non-target tissues exhibiting low specificity protein expression. Ongoing studies with betulinic acid are investigating tumor-type similarities and more potent formulations for possible new chemotherapeutic agents.

Citation: Chintharlapalli S, Papineni S, Ramaiah SK, Safe S( Exit NIEHS. 2007. Betulinic acid inhibits prostate cancer growth through inhibition of specificity protein transcription factors. Cancer Res 7(6):2816-2823.

Remodeling Complex Activates Nucleosomes for Migration to Chromatin

Repair of double strand breaks (DSBs) in DNA protects organisms by maintaining the integrity of their genomic structures. The most serious type of DNA damage, DSBs occur in chromatin, the tightly wound complexes of DNA and associated proteins known as histones that enable DNA to fit into a smaller volume within the cellular nucleus. Previous research has implicated histone modification and chromatin remodeling in the recognition and repair of DSBs; however, the nature of the remodeling and how it affects DSBs are not fully understood.

NIEHS-funded researchers recently discovered a chromatin alteration caused by a single DSB generated by an enzyme known as Ho endonuclease. The experiments were carried out using Saccharomyces cerevisiae, a well-known yeast model. The break causes rapid migration to the damage site of nucleosomes, which form histone-free DNA 200-300 base pairs in length adjacent to the break. Additional experiments determined that blocking a key chromatin structure remodeling complex (RSC) or deleting RSC2 severely reduced chromatin remodeling.

Ionizing radiation and oxidative free radicals, agents humans are exposed to every day, can cause breaks in both strands of DNA. The investigators conclude that RSC is vital for efficient DSB repair by mediating chromatin remodeling at the site of the break and allowing the repair machinery access.

Citation: Shim EY, Hong SJ, Oum JH, Yanez Y, Zhang Y, Lee SE( Exit NIEHS. 2007. RSC mobilizes nucleosomes to improve accessibility of repair machinery to the damaged chromatin. Mol Cell Biol 27(5):1602-1613.

Dietary Antioxidant Flavonoids Protect Against Post-Menopausal Breast Cancer

Flavonoids, also called bioflavonoids, are a class of plant compounds most commonly known for their antioxidant properties. They are commonly found in citrus fruits, green tea and grape skins. Previous research suggests that flavonoids have anti-carcinogenic properties. Research conducted as a part of the Long Island Breast Cancer Study Project shows that dietary flavonoid intake is associated with a decreased risk of breast cancer in post-menopausal women.

The study examined a total of 1,434 cases of breast cancer along with 1,440 controls. Cases and controls were interviewed regarding known and suspected risk factors for breast cancer and were asked to complete a food frequency questionnaire. The researchers found a decrease in breast cancer risk associated with dietary flavonoid intake which was stronger for post-menopausal women. The reduced risk varied from about 25 percent to 50 percent based on the type of flavonoid consumed.

Numerous laboratory studies show that flavonoids are able to inhibit aromatase, a key enzyme in the production of estrogen, inhibit tumor cell proliferation and decrease the production of reactive oxygen compounds. All of these mechanisms are thought to influence breast cancer development. This study suggests that post-menopausal women could reduce their risk of developing breast cancer by eating foods or drinking beverages containing flavonoids.

Citation: Fink BN, Steck SE, Wolff MS, Britton JA, Kabat GC, Schroeder JC, Teitelbaum SL, Neugut AI, Gammon MD( Exit NIEHS. 2007. Dietary flavonoid intake and breast cancer risk among women on Long Island. Am J Epidemiol 165(5):514-523.

Glutathione Gene Polymorphism Protects Against Pancreatic Cancer in Elderly

Each year in the United States, nearly 34,000 people are diagnosed with pancreatic cancer and some 32,000 of them will die within five years of diagnosis with about half dying within 6 months. The only known risk factor for the malignancy is smoking, and very little is known about how genetic and environmental factors interact to lead to the disease.

An NIEHS-funded team of investigators hypothesized that genetic variations in the detoxifying enzyme glutathione S-transferase (GST) affect the detoxification of carcinogenic agents and chemotherapeutic agents in the pancreas, thus impacting the risk and survival of pancreatic cancer. They studied 352 pancreatic cancer patients and matched them to 315 healthy control subjects.

The study results show that older individuals with the GST polymorphism known as GSTP1*C had a reduced risk, and in 5-flurouracil treated patients, those with the GSTP1*C lived significantly longer, about six months. This study is believed to be the first to suggest a protective effect of GSTP1 polymorphisms in pancreatic cancer.

The authors conclude that genetic polymorphisms of GSTP1 could be one of several possible mechanisms that modify the risk of pancreatic cancer in older people and may affect the survival rate.

Citation: Jiao L, Bondy ML, Hassan MM, Chang DZ, Abbruzzese JL, Evans DB, Smolensky MH, Li D( Exit NIEHS. 2007. Glutathione S-transferase gene polymorphisms and risk and survival of pancreatic cancer. Cancer 109(5):840-848.

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