Sandur Santosh K, Ichikawa Haruyo, Sethi Gautam, Ahn Kwang Seok, Aggarwal Bharat B
Cytokine Research Laboratory, Department of Experimental Therapeutics, Unit 143, the University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030.
Cytokine Research Laboratory, Department of Experimental Therapeutics, Unit 143, the University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030.
J Biol Chem. 2006 Jun 23;281(25):17023-17033. doi: 10.1074/jbc.M601595200. Epub 2006 Apr 19.
Plumbagin, derived from the medicinal plant Plumbago zeylanica, modulates cellular proliferation, carcinogenesis, and radioresistance, all known to be regulated by the activation of the transcription factor NF-kappaB, suggesting plumbagin might affect the NF-kappaB activation pathway. We found that plumbagin inhibited NF-kappaB activation induced by TNF, and other carcinogens and inflammatory stimuli (e.g. phorbol 12-myristate 13-acetate, H2O2, cigarette smoke condensate, interleukin-1beta, lipopolysaccharide, and okadaic acid). Plumbagin also suppressed the constitutive NF-kappaB activation in certain tumor cells. The suppression of NF-kappaB activation correlated with sequential inhibition of the tumor necrosis factor (TNF)-induced activation of IkappaBalpha kinase, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation, p65 nuclear translocation, and the NF-kappaB-dependent reporter gene expression activated by TNF, TNFR1, TRAF2, NIK, IKK-beta, and the p65 subunit of NF-kappaB. Plumbagin also suppressed the direct binding of nuclear p65 and recombinant p65 to the DNA, and this binding was reversed by dithiothreitol both in vitro and in vivo. However, plumbagin did not inhibit p65 binding to DNA when cells were transfected with the p65 plasmid containing cysteine 38 mutated to serine. Plumbagin down-regulated the expression of NF-kappaB-regulated anti-apoptotic (IAP1, IAP2, Bcl-2, Bcl-xL, cFLIP, Bfl-1/A1, and survivin), proliferative (cyclin D1 and COX-2), and angiogenic (matrix metalloproteinase-9 and vascular endothelial growth factor) gene products. This led to potentiation of apoptosis induced by TNF and paclitaxel and inhibited cell invasion. Overall, our results indicate that plumbagin is a potent inhibitor of the NF-kappaB activation pathway that leads to suppression of NF-kappaB-regulated gene products. This may explain its cell growth modulatory, anticarcinogenic, and radiosensitizing effects previously described.
白花丹素源自药用植物白花丹，可调节细胞增殖、致癌作用和放射抗性，所有这些都已知受转录因子核因子-κB（NF-κB）激活的调控，这表明白花丹素可能影响NF-κB激活途径。我们发现白花丹素可抑制由肿瘤坏死因子（TNF）以及其他致癌物和炎性刺激物（如佛波酯12-肉豆蔻酸酯13-乙酸酯、过氧化氢、香烟烟雾浓缩物、白细胞介素-1β、脂多糖和冈田酸）诱导的NF-κB激活。白花丹素还可抑制某些肿瘤细胞中组成型NF-κB的激活。NF-κB激活的抑制与肿瘤坏死因子（TNF）诱导的IκBα激酶激活、IκBα磷酸化、IκBα降解、p65磷酸化、p65核转位以及由TNF、TNFR1、TRAF2、NIK、IKK-β和NF-κB的p65亚基激活的NF-κB依赖性报告基因表达的顺序抑制相关。白花丹素还可抑制核p65和重组p65与DNA的直接结合，并且在体外和体内二硫苏糖醇均可逆转这种结合。然而，当用含有突变为丝氨酸的半胱氨酸38的p65质粒转染细胞时，白花丹素并不抑制p65与DNA的结合。白花丹素下调NF-κB调控的抗凋亡（IAP1、IAP2、Bcl-2、Bcl-xL、cFLIP、Bfl-1/A1和存活素）、增殖（细胞周期蛋白D1和COX-2）和血管生成（基质金属蛋白酶-9和血管内皮生长因子）基因产物的表达。这导致TNF和紫杉醇诱导的凋亡增强并抑制细胞侵袭。总体而言，我们的结果表明白花丹素是NF-κB激活途径的有效抑制剂，可导致NF-κB调控的基因产物受到抑制。这可能解释了其先前所述的细胞生长调节、抗癌和放射增敏作用。
