Nimbolide, a limonoid triterpene, inhibits growth of human colorectal cancer xenografts by suppressing the proinflammatory microenvironment.
Nimbolide, a limonoid triterpene, inhibits growth of human colorectal cancer xenografts by suppressing the proinflammatory microenvironment.
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DOI：
10.1158/1078-0432.ccr-13-0080
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发表时间：
2013-08-15
期刊：
影响因子：
--
通讯作者：
Aggarwal BB
中科院分区：
文献类型：
--
作者：
Gupta SC;Prasad S;Sethumadhavan DR;Nair MS;Mo YY;Aggarwal BB
过去十年的广泛研究表明，促炎微环境在结直肠癌（CRC）的发展中起着关键作用。在本研究中，研究了一种柠檬苦素类三萜类化合物--印楝内酯是否能抑制结直肠癌的生长。采用MTT法检测Nimbolide对结直肠癌细胞增殖的影响，采用caspase激活法和多聚ADP核糖聚合酶切割法检测Nimbolide对结直肠癌细胞凋亡的影响，采用DNA结合法检测NF-kappa B（NF-kB）激活的影响，采用Western blotting法检测Nimbolide对结直肠癌细胞蛋白表达的影响。在裸小鼠模型的CRC异种移植物中检查了印宝莱对体内肿瘤生长的影响。Nimbolide可抑制CRC细胞增殖、诱导凋亡、抑制NF-κB活化和NF-κ B调节的致瘤蛋白。Nimbolide抑制NF-κB活化是通过依次抑制IκB激酶（IKK）活化、IκBα磷酸化和p65核转位引起的。此外，还发现印楝内酯对IKK活性的影响是直接的。在体内，在肿瘤接种后腹膜内注射的宁勃利特（5和20 mg/kg体重）显著降低了CRC异种移植物的体积。柠檬苦素处理的异种移植物表现出参与肿瘤细胞存活（Bcl-2、Bcl-xL、c-IAP-1、存活素、Mcl-1）、增殖（c-Myc、细胞周期蛋白D1）、侵袭（MMP-9、ICAM-1）、转移（CXCR 4）和血管生成（VEGF）的蛋白质表达的显著下调。柠檬苦素类化合物被发现在治疗小鼠的血浆和肿瘤组织中是生物可利用的。我们的研究提供的证据表明，印楝内酯可以通过调节促炎微环境来抑制人类CRC的生长。
Extensive research over the past decade has revealed that the proinflammatory microenvironment plays a critical role in the development of colorectal cancer (CRC). Whether nimbolide, a limonoid triterpene, can inhibit the growth of CRC was investigated in the present study. The effect of nimbolide on proliferation of CRC cell lines was examined by MTT assay, apoptosis by caspase activation and poly-ADP ribose polymerase cleavage, nuclear factor-kappa B (NF-kB) activation by DNA-binding assay, and protein expression by Western blotting. The effect of nimbolide on the tumor growth in vivo was examined in CRC xenografts in a nude mouse model. Nimbolide inhibited proliferation, induced apoptosis, and suppressed NF-κB activation and NF-κB–regulated tumorigenic proteins in CRC cells. The suppression of NF-κB activation by nimbolide was caused by sequential inhibition of IκB kinase (IKK) activation, IκBα phosphorylation, and p65 nuclear translocation. Furthermore, the effect of nimbolide on IKK activity was found to be direct. In vivo, nimbolide (at 5 and 20 mg/kg body weight), injected intraperitoneally after tumor inoculation, significantly decreased the volume of CRC xenografts. The limonoid-treated xenografts exhibited significant down-regulation in the expression of proteins involved in tumor cell survival (Bcl-2, Bcl-xL, c-IAP-1, survivin, Mcl-1), proliferation (c-Myc, cyclin D1), invasion (MMP-9, ICAM-1), metastasis (CXCR4), and angiogenesis (VEGF). The limonoid was found to be bioavailable in the blood plasma and tumor tissues of treated mice. Our studies provide evidence that nimbolide can suppress the growth of human CRC through modulation of the proinflammatory microenvironment.