Anti-proliferative and proapoptotic effects of (-)-epigallocatechin-3-gallate on human melanoma: Possible implications for the chemoprevention of melanoma
Anti-proliferative and proapoptotic effects of (-)-epigallocatechin-3-gallate on human melanoma: Possible implications for the chemoprevention of melanoma
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DOI：
10.1002/ijc.20785
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发表时间：
2005-04-20
影响因子：
6.4
通讯作者：
Wood, GS
中科院分区：
文献类型：
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作者：
Nihal, M;Ahmad, N;Wood, GS
黑色素瘤仅占所有皮肤癌病例的4%左右，但占皮肤癌相关死亡的大部分。标准的全身治疗，如干扰素（IFN）在黑色素瘤的管理中并不充分有效。因此，需要新的方法来预防和治疗这种疾病。食品和饮料中天然存在的化学预防剂对某些癌症（包括非黑色素瘤皮肤癌）有好处。在这里，采用2个人黑色素瘤细胞系（A375无色素性恶性黑色素瘤和Hs-294 T转移性黑色素瘤）和正常人表皮黑色素细胞（NHEM），我们研究了表没食子儿茶素没食子酸酯（EGCG），主要的多酚类抗氧化剂存在，在绿色茶的抗增殖作用。发现EGCG处理导致两种黑素瘤细胞系的活力和生长的剂量依赖性降低。有趣的是，在相似的EGCG浓度下，正常的黑素细胞不受影响。黑色素瘤细胞系的EGCG处理导致细胞增殖降低（如通过Ki-67和PCNA蛋白水平评估的）和细胞凋亡诱导（如通过PARP切割、TUNEL测定和JC-1测定评估的）。EGCG还显著抑制所研究的黑色素瘤细胞的殖民地形成能力。黑色素瘤细胞的EGCG处理导致抗凋亡蛋白Bcl 2的下调、促凋亡Bax的上调和半胱天冬酶-3、-7和-9的活化。此外，我们的数据表明，EGCG治疗导致细胞周期蛋白D1和cdk 2蛋白水平的显着的，剂量依赖性的降低和诱导细胞周期蛋白激酶抑制剂（ckis）p16（INK 4a），p21（WAF 1/CIP 1）和p27（KIP 1）。我们的数据表明，表没食子儿茶素没食子酸酯引起显著诱导细胞周期停滞和黑色素瘤细胞的凋亡，这是通过调节cki-细胞周期蛋白-cdk网络和Bcl 2家族蛋白介导的。因此，EGCG单独或与目前的治疗方法结合，可用于黑色素瘤的管理。(C)2004 Wiley-Liss，Inc.
Melanoma accounts for only about 4% of all skin cancer cases but most of skin cancer-related deaths. Standard systemic therapies such as interferon (IFN) have not been adequately effective in the management of melanoma. Therefore, novel approaches are needed for prevention and treatment of this disease. Chemoprevention by naturally occurring agents present in food and beverages has shown benefits in certain cancers including nonmelanoma skin cancers. Here, employing 2 human melanoma cell lines (A375 amelanotic malignant melanoma and Hs-294T metastatic melanoma) and normal human epidermal melanocytes (NHEM), we studied the antiproliferative effects of epigallocatechin-3-gallate (EGCG), the major polyphenolic antioxidant present,in green tea. EGCG treatment was found to result in a dose-dependent decrease in the viability and growth of both melanoma cell lines. Interestingly, at similar, EGCG concentrations, the normal melanocytes were not affected. EGCG treatment of the melanoma cell lines resulted in decreased cell proliferation (as assessed by Ki-67 and PCNA protein levels) and induction of apoptosis (as assessed cleavage of PARP, TUNEL assay and JC-1 assay). EGCG also significantly inhibited the colony formation ability of the melanoma cells studied. EGCG treatment of melanoma cells resulted in a downmodulation of anti-apoptotic protein Bcl2, upregulation of proapoptotic Bax and activation of caspases -3, -7 and -9. Furthermore, our data demonstrated that EGCG treatment resulted in a significant, dose-dependent decrease in cyclin D1 and cdk2 protein levels and induction of cyclin kinase inhibitors (ckis) p16(INK4a), p21(WAF1/CIP1) and p27(KIP1). Our data suggest that EGCG causes significant induction of cell cycle arrest and apoptosis of melanoma cells that is mediated via modulations in the cki-cyclin-cdk network and Bcl2 family proteins. Thus, EGCG, alone or in conjunction with current therapies, could be useful for the management of melanoma. (C) 2004 Wiley-Liss, Inc.