Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
Int J Cancer. 2010 Jul 15;127(2):257-68. doi: 10.1002/ijc.25041.
Gemcitabine, while a standard treatment of advanced pancreatic cancer (PaCa), alone is not very effective. New agents that are safe and effective are highly needed. Resveratrol is one such agent which is safe and multitargeted; and has been linked with suppression of survival, proliferation, invasion and angiogenesis of cancer. Whether resveratrol can sensitize PaCa to gemcitabine in vitro and in vivo was investigated. We established PaCa xenografts in nude mice, randomized into 4 groups, and treated with vehicle, gemcitabine, resveratrol and with combination. Modulation of NF-kappaB and markers of proliferation, angiogenesis and invasion were ascertained using electrophoretic mobility shift assay (EMSA), immunohistochemistry and western blot analysis. Resveratrol inhibited the proliferation of 4 different human PaCa cell lines, synergized the apoptotic effects of gemcitabine, inhibited the constitutive activation of NF-kappaB and expression of bcl-2, bcl-xL, COX-2, cyclin D1 MMP-9 and VEGF. In an orthotopic model of human PaCa, we found that resveratrol significantly suppressed the growth of the tumor (p < 0.001) and this effect was further enhanced by gemcitabine (p < 0.001). Both the markers of proliferation index Ki-67 and the micro vessel density CD31 were significantly downregulated in tumor tissue by the combination of gemcitabine and resveratrol (p < 0.001 vs. control; p < 0.01 vs. gemcitabine). As compared to vehicle control, resveratrol also suppressed the NF-kappaB activation and expression of cyclin D1, COX-2, ICAM-1, MMP-9 and survivin. Overall our results demonstrate that resveratrol can potentiate the effects of gemcitabine through suppression of markers of proliferation, invasion, angiogenesis and metastasis.
吉西他滨是晚期胰腺癌（PaCa）的标准治疗方法，但单独使用效果并不理想。因此，急需安全有效的新药物。白藜芦醇就是这样一种安全的多靶点药物，它与抑制癌症的生存、增殖、侵袭和血管生成有关。本研究旨在探讨白藜芦醇能否在体外和体内增强吉西他滨对 PaCa 的作用。我们建立了裸鼠的 PaCa 异种移植模型，将其随机分为 4 组，分别给予载体、吉西他滨、白藜芦醇和联合治疗。采用电泳迁移率变动分析（EMSA）、免疫组化和 Western blot 分析来确定 NF-κB 和增殖、血管生成和侵袭标志物的变化。白藜芦醇抑制了 4 种不同的人 PaCa 细胞系的增殖，与吉西他滨协同诱导凋亡，抑制 NF-κB 的组成性激活和 bcl-2、bcl-xL、COX-2、cyclin D1、MMP-9 和 VEGF 的表达。在人 PaCa 的原位模型中，我们发现白藜芦醇显著抑制肿瘤生长（p < 0.001），且与吉西他滨联合使用时效果进一步增强（p < 0.001）。Ki-67 增殖指数标志物和 CD31 微血管密度在肿瘤组织中的表达均显著下调（p < 0.001 与对照组相比；p < 0.01 与吉西他滨组相比）。与对照组相比，白藜芦醇还抑制了 NF-κB 的激活和 cyclin D1、COX-2、ICAM-1、MMP-9 和 survivin 的表达。总的来说，我们的结果表明，白藜芦醇可以通过抑制增殖、侵袭、血管生成和转移标志物来增强吉西他滨的作用。
