Gururaj Anupama E, Belakavadi Madesh, Venkatesh Deepak A, Marmé Dieter, Salimath Bharathi P
Department of Applied Botany and Biotechnology, University of Mysore, Mysore 570 006, India.
Biochem Biophys Res Commun. 2002 Oct 4;297(4):934-42. doi: 10.1016/s0006-291x(02)02306-9.
Modulation of pathological angiogenesis by curcumin (diferuloylmethane), the active principle of turmeric, seems to be an important possibility meriting mechanistic investigations. In this report, we have studied the effect of curcumin on the growth of Ehrlich ascites tumor cells and endothelial cells in vitro. Further, regulation of tumor angiogenesis by modulation of angiogenic ligands and their receptor gene expression in tumor and endothelial cells, respectively, by curcumin was investigated. Curcumin, when injected intraperitoneally (i.p) into mice, effectively decreased the formation of ascites fluid by 66% in EAT bearing mice in vivo. Reduction in the number of EAT cells and human umbelical vein endothelial cells (HUVECs) in vitro by curcumin, without being cytotoxic to these cells, is attributed to induction of apoptosis by curcumin, as is evident by an increase in cells with fractional DNA content seen in our results on FACS analysis. However, curcumin had no effect on the growth of NIH3T3 cells. Curcumin proved to be a potent angioinhibitory compound, as demonstrated by inhibition of angiogenesis in two in vivo angiogenesis assay systems, viz. peritoneal angiogenesis and chorioallantoic membrane assay. The angioinhibitory effect of curcumin in vivo was corroborated by the results on down-regulation of the expression of proangiogenic genes, in EAT, NIH3T3, and endothelial cells by curcumin. Our results on Northern blot analysis clearly indicated a time-dependent (0-24h) inhibition by curcumin of VEGF, angiopoietin 1 and 2 gene expression in EAT cells, VEGF and angiopoietin 1 gene expression in NIH3T3 cells, and KDR gene expression in HUVECs. Further, decreased VEGF levels in conditioned media from cells treated with various doses of curcumin (1 microM-1mM) for various time periods (0-24h) confirm its angioinhibitory action at the level of gene expression. Because of its non-toxic nature, curcumin could be further developed to treat chronic diseases that are associated with extensive neovascularization.
姜黄素（二阿魏酰甲烷）是姜黄的活性成分，对病理性血管生成的调节作用似乎是一个值得进行机制研究的重要方向。在本报告中，我们研究了姜黄素对体外艾氏腹水瘤细胞和内皮细胞生长的影响。此外，还研究了姜黄素分别通过调节肿瘤细胞和内皮细胞中血管生成配体及其受体基因表达来调控肿瘤血管生成的情况。姜黄素经腹腔注射到小鼠体内后，能有效降低荷艾氏腹水瘤小鼠体内腹水的形成，降幅达66%。姜黄素在体外可减少艾氏腹水瘤细胞和人脐静脉内皮细胞（HUVECs）的数量，且对这些细胞无细胞毒性，这归因于姜黄素诱导细胞凋亡，流式细胞术分析结果显示DNA含量分数的细胞数量增加就证明了这一点。然而，姜黄素对NIH3T3细胞的生长没有影响。姜黄素被证明是一种有效的血管生成抑制化合物，这在两种体内血管生成检测系统中得到了证实，即腹膜血管生成和绒毛尿囊膜检测。姜黄素在体内的血管生成抑制作用通过其对艾氏腹水瘤、NIH3T3和内皮细胞中促血管生成基因表达下调的结果得到了证实。我们的Northern印迹分析结果清楚地表明，姜黄素对艾氏腹水瘤细胞中VEGF、血管生成素1和2基因表达、NIH3T3细胞中VEGF和血管生成素1基因表达以及HUVECs中KDR基因表达具有时间依赖性（0 - 24小时）抑制作用。此外，用不同剂量的姜黄素（1 microM - 1mM）处理细胞不同时间段（0 - 24小时）后，条件培养基中VEGF水平降低，这证实了其在基因表达水平上的血管生成抑制作用。由于姜黄素无毒，因此可以进一步开发用于治疗与广泛新血管形成相关的慢性疾病。
