Mee Young Hong

Pomegranate polyphenols down-regulate expression of androgen-synthesizing genes in human prostate cancer cells overexpressing the androgen receptor☆

Prostate cancer is dependent on circulating testosterone in its early stages and is treatable with radiation and surgery. However, recurrent prostate tumors advance to an androgen-independent state in which they progress in the absence of circulating testosterone, leading to metastasis and death. During the development of androgen independence, prostate cancer cells are known to increase intracellular testosterone synthesis, which maintains cancer cell growth in the absence of significant amounts of circulating testosterone. Overexpression of the androgen receptor (AR) occurs in androgen-independent prostate cancer and has been proposed as another mechanism promoting the development of androgen independence. The LNCaP-AR cell line is engineered to overexpress AR but is otherwise similar to the widely studied LNCaP cell line. We have previously shown that pomegranate extracts inhibit both androgen-dependent and androgen-independent prostate cancer cell growth. In this study, we examined the effects of pomegranate polyphenols, ellagitannin-rich extract and whole juice extract on the expression of genes for key androgen-synthesizing enzymes and the AR. We measured expression of the HSD3B2 (3beta-hydroxysteroid dehydrogenase type 2), AKR1C3 (aldo-keto reductase family 1 member C3) and SRD5A1 (steroid 5alpha reductase type 1) genes for the respective androgen-synthesizing enzymes in LNCaP, LNCaP-AR and DU-145 human prostate cancer cells. A twofold suppression of gene expression was considered statistically significant. Pomegranate polyphenols inhibited gene expression and AR most consistently in the LNCaP-AR cell line (P=.05). Therefore, inhibition by pomegranate polyphenols of gene expression involved in androgen-synthesizing enzymes and the AR may be of particular importance in androgen-independent prostate cancer cells and the subset of human prostate cancers where AR is up-regulated.

Chinese Red Yeast Rice Versus Lovastatin Effects on Prostate Cancer Cells With and Without Androgen Receptor Overexpression

Chinese red yeast rice (RYR), a food herb made by fermenting Monascus purpureus Went yeast on white rice, contains a mixture of eight different monacolins that inhibit cholesterogenesis and also red pigments with antioxidant properties. Monacolin K (MK) is identical to lovastatin (LV). Both LV and RYR contain statins, which could inhibit de novo cholesterogenesis, which is critical to the growth of tumor cells. Dysregulation of the cholesterol biosynthetic pathway has been demonstrated during progression to androgen independence in xenograft models, and it has been proposed that cholesterogenesis and androgen receptor (AR) up-regulation are essential to androgen-independent cell survival. This study was designed to examine the differences between the effects of RYR and LV on androgen-dependent LNCaP cells and androgen-independent cells overexpressing AR (LNCaP-AR). RYR showed more potent inhibition effect on prostate cancer cell growth compared to LV. Both the pigment and monacolin-enriched fractions purified from RYR inhibited proliferation (P < .001) to a lesser extent than intact RYR. While mevalonate, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), restored proliferation in LV-treated cells, it failed to do so in RYR-treated cells. Expression of the HMGCR gene was up-regulated by LV (P < .001) but not RYR in both LNCaP and LNCaP-AR cells. These results suggest that the RYR matrix beyond MK alone may be bioactive in inhibiting androgen-dependent and -independent prostate cancer growth. In vivo studies are needed to further establish the potential advantages of RYR over LV in prostate cancer chemoprevention and in the prevention of the emergence of androgen independence.

The Protective Effects of Green Tea Polyphenols: Lipid Profile, Inflammation, and Antioxidant Capacity in Rats Fed an Atherogenic Diet and Dextran Sodium Sulfate

Acute and chronic inflammation and dyslipidemia play a critical role in the development of various diseases, including cardiovascular disease. Green tea polyphenols possess potent antioxidative and anti-inflammatory properties that contribute to the beneficial effects on heart health. The present study was carried out to determine if administration of a green tea extract (Polyphenon(®) E [PPE]; Mitsui Norin Co., Ltd., Tokyo, Japan) at 0.2% in the diet reduces cardiovascular risk factors, including dyslipidemia, inflammation, adiposity, and oxidative stress, in rats fed an atherogenic (high fat, cholesterol, and sugar) diet with dextran sodium sulfate (DSS) in drinking water. DSS treatment increased serum total cholesterol, low-density lipoprotein (LDL)-cholesterol, C-reactive proteins (CRP), and markers of liver toxicity and decreased high-density lipoprotein (HDL)-cholesterol significantly. Adding PPE to the atherogenic diet (PPE-diet) was associated with lower total cholesterol and LDL-cholesterol (P<.001) and increased HDL-cholesterol (P=.001). In addition, the PPE-diet was associated with decreased serum CRP concentration (P=.023) and increased total antioxidant capacity (P=.016) and catalase (P=.001) and glutathione peroxidase (P=.050) activities. The PPE-diet significantly lowered epididymal fat pad weight (P=.009). Feeding the PPE-diet also ameliorated some of the DSS-induced lipid, inflammatory, and oxidative symptoms. In summary, green tea supplementation decreased several cardiovascular risk factors, including body composition, dyslipidemia, inflammatory status, and antioxidant capacity, in rats fed an atherogenic diet. This study supports green tea as an effective dietary component for sustaining cardiovascular health.

Chinese Red Yeast Rice Inhibition of Prostate Tumor Growth in SCID Mice

Prostate cancer is a slowly developing but very common cancer in males that may be amenable to preventive strategies that are not toxic. Chinese red yeast rice (RYR), a food herb made by fermenting Monascus purpureus Went yeast on white rice, contains a mixture of eight different monacolins that inhibit cholesterogenesis in addition to red pigments with antioxidant properties. Monacolin K is identical to lovastatin (LV), but LV unlike RYR can be used in individuals intolerant to statins due to muscle pain. Both LV and RYR inhibit de novo cholesterogenesis, which is critical to the growth of tumor cells. Long-term use of statin drugs has been associated with a reduced risk of prostate cancer. We have previously shown that RYR inhibited androgen-dependent and androgen receptor–overexpressing androgen-independent prostate cancer cell proliferation in vitro. This study was designed to determine whether RYR and LV inhibit prostate tumor growth in SCID mice. RYR significantly reduced tumor volumes of androgen-dependent and androgen-independent prostate xenograft tumors compared with animals receiving vehicle alone (P < 0.05). Inhibition by RYR was greater than that observed with LV at the dose found in RYR, showing that other compounds in RYR contributed to the antiproliferative effect. There was a significant correlation of tumor volume to serum cholesterol (P < 0.001). RYR decreased gene expression of androgen synthesizing enzymes (HSD3B2, AKR1C3, and SRD5A1) in both type of tumors (P < 0.05). Clinical studies of RYR for prostate cancer prevention in the increasing population of men undergoing active surveillance should be considered. Cancer Prev Res; 4(4); 608–15. ©2011 AACR.