Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-κB-regulated gene products
Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-κB-regulated gene products
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DOI：
10.1158/0008-5472.can-06-4257
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发表时间：
2007-04-15
期刊：
影响因子：
11.2
通讯作者：
Aggarwal, Bharat B.
中科院分区：
文献类型：
--
作者：
Kunnumakkara, Ajaikumar B.;Guha, Sushovan;Aggarwal, Bharat B.
吉西他滨是目前胰腺癌的最佳治疗方法，但随着时间的推移，这种疾病会对这种药物产生耐药性。胰腺癌的治疗需要能够增强吉西他滨的作用或克服对该药物的化学抗性的药物。姜黄素是姜黄（Curcuma longa）的一种成分，是一种已经显示出抑制转录因子核因子-κ B（NF-κ B）的试剂，其涉及增殖、存活、血管生成和化学抗性。在这项研究中，我们研究了姜黄素是否可以在体外和体内增敏胰腺癌吉西他滨。在体外，姜黄素抑制各种胰腺癌细胞系的增殖，增强吉西他滨诱导的凋亡，并抑制细胞中的组成性NF-κ B活化。在体内，注射胰腺癌细胞并联合使用姜黄素和吉西他滨治疗的裸鼠肿瘤体积显著减小（P = 0.008 vs对照组; P = 0.036 vs吉西他滨单药），Ki-67增殖指数（与对照组相比P = 0.030）、NF-κ B B活化和NF-κ B调节基因产物的表达（细胞周期蛋白D1、c-myc、Bcl-2、Bcl-xL、细胞凋亡抑制蛋白-1、环氧合酶-2、基质金属蛋白酶和血管内皮生长因子）与仅用橄榄油处理的对照小鼠的肿瘤进行比较。联合治疗在抑制血管生成方面也非常有效，如CD 31（+）微血管密度降低所示（与对照组相比P = 0.018）。总之，我们的研究结果表明，姜黄素通过抑制增殖、血管生成、NF-κ B和NF-κ B调节的基因产物来增强吉西他滨在胰腺癌中的抗肿瘤作用。
Gemcitabine is currently the best treatment available for pancreatic cancer, but the disease develops resistance to the drug over time. Agents that can either enhance the effects of gemcitabine or overcome chemoresistance to the drug are needed for the treatment of pancreatic cancer. Curcumin, a component of turmeric (Curcuma longa), is one such agent that has been shown to suppress the transcription factor nuclear factor-kappa B (NF-kappa B), which is implicated in proliferation, survival, angiogenesis, and chemoresistance. In this study, we investigated whether curcumin can sensitize pancreatic cancer to gemcitabine in vitro and in vivo. In vitro, curcumin inhibited the proliferation of various pancreatic cancer cell lines, potentiated the apoptosis induced by gemcitabine, and inhibited constitutive NF-kappa B activation in the cells. In vivo, tumors from nude mice injected with pancreatic cancer cells and treated with a combination of curcumin and gemcitabine showed significant reductions in volume (P = 0.008 versus control; P = 0.036 versus gemcitabine alone), Ki-67 proliferation index (P = 0.030 versus control), NF-kappa B activation, and 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, and vascular endothelial growth factor) compared with tumors from control mice treated with olive oil only. The combination treatment was also highly effective in suppressing angiogenesis as indicated by a decrease in CD31(+) microvessel density (P = 0.018 versus control). Overall, our results suggest that curcumin potentiates the antitumor effects of gemcitabine in pancreatic cancer by suppressing proliferation, angiogenesis, NF-kappa B, and NF-kappa B-regulated gene products.