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GSE and skin cancer.
According to the American Cancer Society, >1 million new cases of basal and squamous cell cancers occur annually in the United States alone. Major etiological factors for skin cancer are family history, sun sensitivity, chronic exposure to sun and occupational exposure to carcinogens, and immune suppression. Whereas several efforts have been made to educate the general population about the strategies to prevent skin cancer, such as avoiding exposure to sun and use of sunscreens, additional approaches are still needed to control and prevent the occurrence of skin cancer. In our first study by Zhao et al. with GSE, we assessed the anti-tumor–promoting effect of GSE polyphenolic fraction (GSP) in a 2-stage SENCAR mouse skin carcinogenesis model where a single 7,12-dimethylbenz[a]anthracene (DMBA) application was used as a tumor-initiating event and repeated 12-O-tetradecanoylphorbol 13-acetate application was used as a tumor-promoting event. Topical application of GSP to the DMBA-initiated dorsal mouse skin resulted in a highly significant inhibition of 12-O-tetradecanoylphorbol 13-acetate-caused skin tumor promotion, as evidenced by a significant reduction in tumor incidence, tumor multiplicity, and tumor volume. We found that procyanidin B5–3′-gallate was the most potent antioxidant compared with other polyphenols isolated from the extract by HPLC . Bomser et al. also reported antitumor-promoting activity of GSP in a CD-1 mouse model by mechanisms
In a UVB radiation-induced mouse skin carcinogenesis model, dietary feeding of GSP was effective in preventing photocarcinogenesis at both initiation and promotion stages and malignant transformation of skin papillomas to carcinomas The mechanisms of chemopreventive effects of GSP against UVB-induced skin carcinogenesis .a Together, the studies summarized above provide clear evidence for the potential chemopreventive efficacy of GSE/proanthocyanidins against skin cancer with some mechanistic insights.
GSE and colorectal cancer.
Colon cancer is the 3rd most prevalent cancer in both men and women and accounts for 9% of total deaths due to cancers of all organ sites . Colorectal cancer is preventable, as healthy changes in life style especially in dietary habits could help reduce the risk of this malignancy. Thus, nutritional recommendations from the American Cancer Society include adequate intake of fruits and vegetable in a regular diet .
In our efforts to evaluate the chemopreventive potential of GSE against colorectal cancer, we investigated its in vitro and in vivo anticancer effects in LoVo and HT-29 human colorectal carcinoma cell lines . Our completed studies showed that GSE halts the growth of these cancer cells and, more importantly, inhibits the growth of HT-29 cells in culture as well as when grown as tumor xenografts in athymic nude mice . In animal models for colon cancer chemoprevention, grape seed proanthocyanidins significantly inhibited azoxymethane-induced colonic aberrant crypt foci, a precursor lesion for colon cancer in rat dual-organ tumor model (and reduced the colonic macroscopic and microscopic damage in 2,4,6-trinitrobenzene sulfonic acid-induced ulcerative colitis in rats (.
The anticancer effects of whole black grape (seeds included) extract are also reported in the cancerous colon tissues of humans via inhibition in DNA turnover enzymes (32). The anticancer effects of proanthocyanidins from grape seeds against colon cancer Caco2 cells have also been demonstrated through inhibition of the survival pathway and induction of apoptosis (33). Almost similar anticancer effects of GSE or red wine polyphenolic extract were also observed in HT-29 cells (34).
GSE and prostate cancer.
As per the statistics provided by the American Cancer Society for 2008, prostate cancer (PCA) remains the most commonly diagnosed cancer in men. There has been considerable improvement in the diagnosis and treatment options for PCA patients, which has resulted in stabilization in the rate of incidence of this cancer in recent years (21); however, PCA is still the most deadly malignancy in the elderly male population. Our research program has made major efforts in assessing and establishing chemopreventive and anticancer efficacy of GSE against PCA as summarized in Table 1. In our first study by Agarwal et al. (35) with the DU145 cell line, which represents advanced metastatic hormone refractory human PCA, GSE induced apoptotic death. We also found that GSE inhibited both ligand epidermal growth factor (EGF)-induced and constitutively active EGFR–Shc–ERK1/2–Elk1–AP1 pathway in DU145 cells (36).
Treatment of advanced-stage PCA with chemo- or radiotherapy is often limited by resistance to apoptosis (37). Further, in the advanced stage, PCA cells acquire angiogenic potential, which promotes the growth and metastasis to distant sites. Therefore, agents that can either induce apoptosis or inhibit angiogenic capacity of cancer cells can have profound effects on limiting the progression of cancer to a more advanced stage (37–39). In this regard, we found that GSE exerts antiproliferative and antiangiogenic effects and interferes with IGF-1 signaling in DU145 xenografts by the mechanisms summarized in Table 1, thereby exerting an overall growth inhibitory effect against DU145 xenografts in nude mice (40).
In more detailed mechanistic studies, we observed that GSE inhibits the nuclear factor-κB (NF-κB) pathway and thus results in induction of apoptosis in DU145 cells (41). Constitutive activation of this pathway contributes to the resistance to chemotherapeutic drugs and radiotherapy in various malignancies, including PCA (42,43). Thus, inhibition of this pathway by GSE in DU145 PCA cells could be used as an effective therapeutic target for PCA. In another study with androgen-dependent human PCA LNCaP cells, we observed that GSE causes detachment-induced apoptosis (anoikis) in these cells. The induction of death by GSE in these cells was triggered due to reactive oxygen species induced-DNA damage (44).
In our continued efforts to characterize the chemopreventive efficacy of GSE against PCA, we also conducted the studies in a transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse model, wherein spontaneous neoplastic epithelial transformation occurs in the mouse prostate starting from early lesions of prostatic intraepithelial neoplasia (PIN) to late-stage metastatic adenocarcinoma in a manner that mimics human PCA (45). We observed that oral feeding of GSE to TRAMP mice resulted in higher incidence of PIN with a concomitant decrease in the progression of these initial lesions (PIN) to adenocarcinoma by inhibition of aberrant cell cycle progression (46).
GSE and breast cancer.
Breast cancer is the second leading cause of cancer-related deaths after lung cancer in women. Even though the incidence of breast cancer has declined at a rate of 3.5%/y from 2001 to 2004, the mortality associated with this malignancy is still high (21). Therefore, more efforts are required to develop effective therapeutic or interventive approaches to conquer this malignancy. One effective approach is to target abnormal protein(s) or signaling pathways involved in the progression of this malignancy. One such target could be enzyme aromatase, which is highly expressed in cancerous compared with normal breast tissue (47). Studies conducted by Eng et al. (48) and Kijima et al. (49) revealed that procyanidin dimers, especially procyanidin B2 dimer from wine extract and also found in high quantities in grape seeds, inhibited the activity and expression of this enzyme, which is responsible for the conversion of androgens into estrogens in aromatase-transfected MCF-7 breast cancer cells and their xenografts in athymic nude mice. In another study conducted by Sharma et al. (50), GSE exerted a synergistic effect with doxorubicin in inhibiting the growth of estrogen-receptor–expressing MCF-7 cells as well as estrogen-receptor negative MDA-MB468 cells. The findings of this study revealed that GSE could be used in combination with doxorubicin to enhance the efficacy of this drug (50). Further, cytotoxic effects of IH636 GSE were observed against MCF-7 human breast cancer cells (51). In a chemoprevention setting, supplementation of GSE in rodent diet resulted in a significant reduction in DMBA-induced mammary tumor multiplicity in female rats; however, the protective effect was dependent on the composition of the diet to which it was added (52). Antiangiogenic effects of GSE were observed in MDA-MB-231 human breast cancer cells and in U251 human glioma cells (53). In the study conducted by Mantena et al. (54), the metastatic potential of 4T1 breast cancer cells was inhibited by grape seed proanthocyanidins.
GSE and other cancers.
Apart from the anticancer and chemopreventive efficacy of GSE against skin, colorectal, prostate, and breast cancers discussed above in detail, anticancer efficacy of this extract has also been observed against human lung cancer A427, A549, and H1299 cells, human gastric adenocarcinoma CRL-1739 cells, oral squamous cell carcinoma CAL27 and SCC25 cells, Jurkat, U937, and HL-60 as summarized in Table 1 (51,55–57). GSE as well as red wine have been shown to significantly reduce the number of metastatic nodules on the surface of lung in Swiss mice inoculated with B16F10 melanoma cells, although at a microscopic level, GSE increased the implantation and growth of these cells (58), clearly suggesting that more studies are needed to address these contradictory findings.
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