Division of Radiation Biology, Department of Radiation Oncology, The University of Texas Health Science Center at San Antonio, Greehey Children's Cancer Research Institute, San Antonio, Texas, United States of America.
PLoS One. 2010 Dec 28;5(12):e15627. doi: 10.1371/journal.pone.0015627.
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.
METHODOLOGY/PRINCIPAL FINDINGS: 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(/KIP1), 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.
CONCLUSIONS/SIGNIFICANCE: 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.
白藜芦醇（3,4',5-三羟基二苯乙烯）是一种天然存在的多酚，具有抗炎、抗氧化、心脏保护和抗肿瘤活性。我们最近表明，白藜芦醇可以通过多种机制在体外增强 TRAIL 诱导前列腺癌细胞凋亡的潜力。因此，本研究旨在验证白藜芦醇是否可以在前列腺癌的异种移植模型中增强 TRAIL 诱导凋亡的潜力。
方法/主要发现：白藜芦醇和 TRAIL 单独抑制裸鼠 PC-3 异种移植瘤的生长，通过抑制肿瘤细胞增殖（PCNA 和 Ki67 染色）和诱导凋亡（TUNEL 染色）。白藜芦醇和 TRAIL 的联合使用比单独使用单一药物更能有效抑制肿瘤生长。在异种移植瘤中，白藜芦醇上调了 TRAIL-R1/DR4、TRAIL-R2/DR5、Bax 和 p27（/KIP1）的表达，并抑制了 Bcl-2 和细胞周期蛋白 D1 的表达。单独用白藜芦醇和 TRAIL 治疗的小鼠抑制了血管生成（表现为血管数量减少，以及 VEGF 和 VEGFR2 阳性细胞减少）和转移标志物（MMP-2 和 MMP-9）。与单独使用单一药物相比，白藜芦醇与 TRAIL 的联合使用进一步抑制了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，白藜芦醇抑制了 FKHRL1 的细胞质磷酸化，从而增强了其作为证明的 DNA 结合活性的激活。
结论/意义：这些数据表明，白藜芦醇可以通过激活 FKHRL1 及其靶基因来增强 TRAIL 诱导凋亡的潜力。白藜芦醇抑制肿瘤生长、转移和血管生成以及增强 TRAIL 的治疗潜力表明，白藜芦醇单独或与 TRAIL 联合使用可用于治疗前列腺癌。
