Resveratrol, a multitargeted agent, can enhance antitumor activity of gemcitabine in vitro and in orthotopic mouse model of human pancreatic cancer.
Resveratrol, a multitargeted agent, can enhance antitumor activity of gemcitabine in vitro and in orthotopic mouse model of human pancreatic cancer.
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DOI：
10.1002/ijc.25041
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发表时间：
2010-07-15
影响因子：
6.4
通讯作者：
Aggarwal, Bharat B
中科院分区：
文献类型：
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作者：
Harikumar, Kuzhuvelil B;Kunnumakkara, Ajaikumar B;Sethi, Gautam;Diagaradjane, Parmeswaran;Anand, Preetha;Pandey, Manoj K;Gelovani, Juri;Krishnan, Sunil;Guha, Sushovan;Aggarwal, Bharat B
吉西他滨虽然是晚期胰腺癌(PACA)的标准治疗方法，但单独使用并不十分有效。迫切需要安全有效的新制剂。白藜芦醇就是这样一种安全、多靶点的药物；它与抑制癌症的生存、增殖、侵袭和血管生成有关。研究白藜芦醇在体内外是否能增敏PACA对吉西他滨的敏感性。我们建立了PACA裸鼠移植瘤模型，随机分为4组，分别给予赋形剂、吉西他滨、白藜芦醇及联合用药。通过凝胶迁移率改变分析、免疫组织化学和免疫印迹分析，确定NF-κB的调控以及增殖、血管生成和侵袭的标志物。白藜芦醇抑制4种不同的人PACA细胞株的增殖，协同吉西他滨的促凋亡作用，抑制NF-κB的组成性激活及bcl2、bclxl、cox-2、cyClinD1MMP9和VEGFmRNA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的生长(p<；0.001)，这种作用被吉西他滨进一步增强(p<；0.001)。联合应用吉西他滨和白藜芦醇可显著下调肿瘤组织中增殖指数Ki-67和微血管密度CD31的表达(p<；0.001比对照组；p<；0.01vs吉西他滨)。与空白对照组相比，白藜芦醇还能抑制NF-κB的活化和细胞周期蛋白D1、环氧合酶-2、细胞间黏附分子-1、基质金属蛋白酶-9和Survivin的表达。总体而言，我们的结果表明，白藜芦醇可以通过抑制增殖、侵袭、血管生成和转移的标记物来增强吉西他滨的作用。
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-κB 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-κB 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-κB 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.