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Prostate cancer (PCA) is the most common cancer in elderly men with one out of six men afflicted with this malignancy in the United States. In spite of improvements in diagnostic and therapeutic strategies for PCA, prognosis of this malignancy remains poor at advanced stages suggesting that newer preventive/interventive strategies are required to control this malignancy. Plant based therapies are often used as alternative and complementary treatments for various diseases including cancer. Grape seed extract (GSE) is a rich source of procyanidins and is used as a health supplement in United States. In our previously published studies, we have demonstrated chemopreventive efficacy of this extract per se and of biologically active constituents present in the extract such as gallic acid against PCA. We also demonstrated anti-cancer efficacy of B2-3,3′-di-O-gallate (B2-G2), a di-gallate ester of procyanidin B2 against androgen-independent human PCA DU145 cells. Present study assessed the influence of gallate esterification on the anti-cancer activity of procyanidin B2 (B2) in human PCA LNCaP cells employing B2-3,3′-di-O-gallate (B2-G2), two mono-gallate esters B2-3-O-gallate (B2-3G) and B2-3′-O-gallate (B2-3′G) and the parent compound B2. Since, androgen receptor (AR) is recognized as an important molecular target in early as well as advanced stages of PCA, in the present study, we used human prostate carcinoma LNCaP cells that harbor functional AR and are dependent on androgen for their growth, to investigate the anticancer activity of these compounds. All these compounds were isolated from grape seed extract (GSE) following several chromatographic steps and structures determined by a combination of enzymatic hydrolysis, mass spectrometry and comparisons with standards. We observed that treatment of LNCaP cells with gallate esters B2-G2, B2-3G and B2-3′G significantly decreased LNCaP cell viability; however, B2 and gallic acid were ineffective. Furthermore, only B2-G2 also significantly decreased cell growth. Decreases in cell viability were largely due to apoptosis induction with B2-G2 and B2-3′G exhibiting comparable effects, whereas B2-3G was less effective. In mechanistic studies, B2-G2 and B2-3′G treatments caused caspases-9 and −3 and PARP cleavage, and down-regulated Bcl-2, Bcl-Xl and AR levels. Taken together, our findings demonstrate anti-PCA efficacy of B2-G2 and suggest that a gallate ester moiety at 3′ position of procyanidin B2 contributes more extensively toward the biological activity of the di-gallate ester than esterification of position 3. This study was supported by the National Cancer Institute, NIH RO1 grant CA091883. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5648.

There are 150,000 new cases of colorectal cancer (CRC) each year in the United States alone; one-third of these patients die. Traditional methods of treatment are known to result in severe toxicity suggesting that additional strategies are needed for CRC control. Grape seed extract (GSE); a health supplement rich in polyphenolic compounds has been previously shown by us to exhibit anti-cancer effects in in-vitro and in-vivo models of CRC. In general, as cancer progresses it becomes more resistant to conventional treatments; partly due to resistance to apoptosis, suggesting that the use of agents which are able to induce cancer cell death can be an effective approach to control various malignancies, including CRC. Accordingly, the present study focuses on eluting the efficacy and associated mechanisms of apoptotic death associated with GSE treatment in human CRC cell lines, differing in their metastatic potential. Three human CRC cell lines were chosen based on phenotypic and genetic variations; SW480, SW620 and HCT116, representing cancer stages II-IV, respectively. In SW480 cells, GSE treatment (25-100μg/mL) resulted in a time and a concentration-dependent increase in cell death; from 17-37% death after 12h, to 19-38% after 24h, and maximum of 60% death observed at 48h. Annexin-PI staining revealed that the cell death induced by GSE was apoptotic in nature. At the molecular level, GSE induced caspase-9, −3, and −8 cleavage indicating the involvement of both intrinsic and extrinsic pathways of apoptosis. However, we did not observe any changes in the Bcl-2 family members. Unlike SW480, much lower concentrations of GSE (10-30μg/mL) were effective in causing 50% cell death as early as 12h in SW620 CRC cells, and involved specifically the activation of the extrinsic apoptosis pathway via DR4 up regulation, caspase-8, −3, and PARP cleavage, as a robust mechanism of apoptotic cell death. In HCT116 cells, GSE treatment (10-30μg/mL) resulted in 42-60% death after 12h, which did not increase, significantly, at later time points. Cell death ELISA revealed that almost 60% apoptotic death occurred as early as 12h at 30μg/mL concentration of GSE. Mechanistic studies revealed that GSE activates the intrinsic pathway of apoptosis, via cleavage of caspase-9 and −3. We also observed caspase-8 cleavage with no alteration of Bid levels, indicating secondary activation of this caspase through the intrinsic pathway. Together, these results clearly show that the apoptosis inducing effect of GSE involves both intrinsic and extrinsic pathways, and the apoptotic activity of GSE increases with an increase in the metastatic potential of the CRC cell lines; HCT116 being the most sensitive. In conclusion, our findings further support the notion that GSE could be an effective chemopreventive and chemotherapeutic agent for different stages of colorectal cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5721.

The two major capital market reforms of (i) entry of Foreign Institutional Investors (FIIs) in Indian stock market (ii) permission to Indian companies for raising capital from foreign stock exchanges by means of American Depository Receipts (ADRs) / Global Depository Receipts (GDRs). Further introduction of two-way fungibility in these instruments of ADRs / GDRs leads to reduction of the sovereignty of Indian stock market. As such, Indian stock market now, is not only sensitive to national events but also more sensitive to international events. Due to the speculative motive of FIIs investment, investment by FIIs is subject to frequent reversals. Volatility is a measure of how far the current price of an asset deviates from its average past prices. Investors demand higher risk premium as a compensation for increased risk due to volatility. A higher risk premium implies higher cost of capital and thus lowers investment. The prevailing inefficiency in emerging securities markets including India further magnifies the problem of volatility. In this paper, an effort is made to predict stock return volatility and contribution of FIIs investment to that volatility using high frequency data (daily data).