Resveratrol enhances antitumor activity of TRAIL in prostate cancer xenografts through activation of FOXO transcription factor.
Resveratrol enhances antitumor activity of TRAIL in prostate cancer xenografts through activation of FOXO transcription factor.
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DOI：
10.1371/journal.pone.0015627
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发表时间：
2010-12-28
期刊：
影响因子：
3.7
通讯作者：
Srivastava RK
中科院分区：
文献类型：
--
作者：
Ganapathy S;Chen Q;Singh KP;Shankar S;Srivastava RK
白藜芦醇（3，4′，5-三羟基二苯乙烯）是一种天然存在的多酚类化合物，具有抗炎、抗氧化、心脏保护和抗肿瘤活性。我们最近发现白藜芦醇可以通过多种体外机制增强前列腺癌细胞中TRAIL的凋亡诱导潜力。因此，本研究旨在验证白藜芦醇是否可以增强前列腺癌异种移植模型中TRAIL的促凋亡潜力。白藜芦醇和TRAIL单独通过抑制肿瘤细胞增殖（PCNA和Ki 67染色）和诱导凋亡（TUNEL染色）来抑制PC-3裸鼠移植瘤的生长。白藜芦醇和TRAIL的组合比单独药物更有效地抑制肿瘤生长。白藜芦醇可上调肿瘤细胞TRAIL-R1/DR 4、TRAIL-R2/DR 5、Bax和p27/KIP 1的表达，抑制Bcl-2和cyclin D1的表达。用白藜芦醇和TRAIL单独治疗小鼠抑制血管生成（如通过减少的血管数量以及VEGF和VEGFR 2阳性细胞所证明的）和转移标志物（MMP-2和MMP-9）。白藜芦醇与TRAIL的组合比单独的单药进一步抑制肿瘤中的血管数量和循环内皮生长因子受体2阳性内皮细胞。此外，白藜芦醇抑制FKHRL 1的细胞质磷酸化，导致其增强的激活，如通过增加的DNA结合活性所证明的。这些数据表明，白藜芦醇可以通过激活FKHRL 1及其靶基因来增强TRAIL的凋亡诱导潜力。白藜芦醇能够抑制肿瘤生长、转移和血管生成，并增强TRAIL的治疗潜力，这表明白藜芦醇单独或与TRAIL组合可用于前列腺癌的管理。
Resveratrol (3, 4′, 5 tri-hydroxystilbene), a naturally occurring polyphenol, exhibits anti-inflammatory, antioxidant, cardioprotective and antitumor activities. We have recently shown that resveratrol can enhance the apoptosis-inducing potential of TRAIL in prostate cancer cells through multiple mechanisms in vitro. Therefore, the present study was designed to validate whether resveratrol can enhance the apoptosis-inducing potential of TRAIL in a xenograft model of prostate cancer. Resveratrol and TRAIL alone inhibited growth of PC-3 xenografts in nude mice by inhibiting tumor cell proliferation (PCNA and Ki67 staining) and inducing apoptosis (TUNEL staining). The combination of resveratrol and TRAIL was more effective in inhibiting tumor growth than single agent alone. In xenografted tumors, resveratrol upregulated the expressions of TRAIL-R1/DR4, TRAIL-R2/DR5, Bax and p27/K IP1, and inhibited the expression of Bcl-2 and cyclin D1. Treatment of mice with resveratrol and TRAIL alone inhibited angiogenesis (as demonstrated by reduced number of blood vessels, and VEGF and VEGFR2 positive cells) and markers of metastasis (MMP-2 and MMP-9). The combination of resveratrol with TRAIL further inhibited number of blood vessels in tumors, and circulating endothelial growth factor receptor 2-positive endothelial cells than single agent alone. Furthermore, resveratrol inhibited the cytoplasmic phosphorylation of FKHRL1 resulting in its enhanced activation as demonstrated by increased DNA binding activity. These data suggest that resveratrol can enhance the apoptosis-inducing potential of TRAIL by activating FKHRL1 and its target genes. The ability of resveratrol to inhibit tumor growth, metastasis and angiogenesis, and enhance the therapeutic potential of TRAIL suggests that resveratrol alone or in combination with TRAIL can be used for the management of prostate cancer.
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影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
2.7
作者：
Hamza M;Dionne RA
通讯作者：
Dionne RA
DOI：
10.1042/bj20091857
发表时间：
2010-07-15
期刊：
The Biochemical journal
影响因子：
--
作者：
Calamini B;Ratia K;Malkowski MG;Cuendet M;Pezzuto JM;Santarsiero BD;Mesecar AD
通讯作者：
Mesecar AD
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
16
作者：
Bakker, Walbert J.;Harris, Isaac S.;Mak, Tak W.
通讯作者：
Mak, Tak W.