Curcumin sensitizes human colorectal cancer xenografts in nude mice to γ-radiation by targeting nuclear factor-κB-regulated gene products
Curcumin sensitizes human colorectal cancer xenografts in nude mice to γ-radiation by targeting nuclear factor-κB-regulated gene products
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DOI：
10.1158/1078-0432.ccr-07-4722
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发表时间：
2008-04-01
影响因子：
11.5
通讯作者：
Krishnan, Sunil
中科院分区：
文献类型：
--
作者：
Kunnumakkara, Ajaikumar B.;Diagaradjane, Parmeswaran;Krishnan, Sunil
目的：结直肠癌如何形成对伽马辐射的抵抗力尚不完全清楚，但转录因子核因子 kappa B (NF-kappa B) 和 NF-kappa B 调节的基因产物已被提议作为介质。由于姜黄 (Curcuma longa) 的一种成分姜黄素已被证明可以抑制 NF-kappa B 激活，因此在裸鼠结直肠癌异种移植物中研究了它是否可以使结直肠癌对 γ 辐射敏感。 实验设计：我们在裸鼠中建立了 HCT 116 异种移植物，随机分为四组，并用载体（玉米油）、姜黄素、γ 辐射和姜黄素联合治疗与伽马辐射。使用电泳迁移率变动测定和免疫组织化学确定 NF-κ B 调节。通过免疫组织化学和蛋白质印迹分析监测增殖、血管生成和侵袭标志物。结果：姜黄素通过延长肿瘤再生时间（P = 0.02）和降低 Ki-67 增殖指数（P < 0. 001），显着增强分段放射治疗的疗效。此外，姜黄素抑制 NF-κ B 活性和 NF-κ B 调节基因产物（细胞周期蛋白 D1、c-myc、Bcl-2、Bcl-xL、细胞凋亡蛋白抑制剂 1、环加氧酶 2、基质金属蛋白酶 9 和血管内皮生长因子）的表达，其中许多是由放射治疗诱导的并介导放射抗性。姜黄素和放射治疗的组合也抑制了血管生成，血管内皮生长因子和微血管密度降低表明（与单独放射治疗相比，P = 0.002）。结论：总的来说，我们的结果表明，姜黄素通过抑制 NF-κ B 和 NF-κ B 调节的基因产物，从而抑制增殖和血管生成，从而增强结直肠癌放射治疗的抗肿瘤作用。
Purpose: How colorectal cancer develops resistance to gamma-radiation is not fully understood, but the transcription factor nuclear factor-kappa B (NF-kappa B) and NF-kappa B -regulated gene products have been proposed as mediators. Because curcumin, a component of turmeric (Curcuma longa), has been shown to suppress NF-kappa B activation, whether it can sensitize the colorectal cancer to gamma-radiation was investigated in colorectal cancer xenografts in nude mice.Experimental Design: We established HCT 116 xenograft in nude mice, randomized into four groups, and treated with vehicle (corn oil), curcumin, gamma-radiation, and curcumin in combination with gamma-radiation. NF-kappa B modulation was ascertained using electrophoretic mobility shift assay and immunohistochemistry. Markers of proliferation, angiogenesis, and invasion were monitored by immunohistochemistry and Western blot analysis.Results: Curcumin significantly enhanced the efficacy of fractionated radiation therapy by prolonging the time to tumor regrowth (P = 0.02) and by reducing the Ki-67 proliferation index (P < 0. 001). Moreover, curcumin suppressed NF-kappa B activity and the expression of NF-kappa B -regulated gene products (cyclin D1, c-myc, Bcl-2, Bcl-xL, cellular inhibitor of apoptosis protein-1, cyclooxygenase-2, matrix metalloproteinase-9, and vascular endothelial growth factor), many of which were induced by radiation therapy and mediate radioresistance. The combination of curcumin and radiation therapy also suppressed angiogenesis, as indicated by a decrease in vascular endothelial growth factor and microvessel density (P = 0.002 versus radiation alone).Conclusion: Collectively, our results suggest that curcumin potentiates the antitumor effects of radiation therapy in colorectal cancer by suppressing NF-kappa B and NF-kappa B -regulated gene products, leading to inhibition of proliferation and angiogenesis.