Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
Eur J Pharmacol. 2012 Feb 29;677(1-3):47-54. doi: 10.1016/j.ejphar.2011.12.035. Epub 2011 Dec 29.
Identification of natural products that have antitumor activity is invaluable to the chemoprevention and therapy of cancer. The embryos of lotus (Nelumbo nucifera) seeds are consumed in beverage in some parts of the world for their presumed health-benefiting effects. In this report we studied the effects of neferine, a major alkaloid component in lotus embryos, on human osteosarcoma cells and the underlying mechanisms. We found that neferine possessed a potent growth-inhibitory effect on human osteosarcoma cells, but not on non-neoplastic human osteoblast cells. The inhibitory effect of neferine on human osteosarcoma cells was largely attributed to cell cycle arrest at G1. The induction of G1 arrest was p21(WAF1/CIP1)-dependent, but was independent of p53 or RB (retinoblastoma-associated protein). The up-regulation of p21 by neferine was due to an increase in the half-life of p21 protein. We examined four kinases that are known to affect the stabilization of p21, and found that p38 MAPK and JNK were activated by neferine. However, only SB203580 (an inhibitor of p38), but not SP600125 (the inhibitor of JNK), can attenuate the up-regulation of p21 in response to neferine. Furthermore, the p21-stabilizing effect of neferine was abolished when p38 was silenced by RNA interference. Finally, we showed that neferine treatment led to an increased phosphorylation of p21 at Ser130 that was dependent on p38. Our results for the first time showed a direct antitumor effect of neferine, suggesting that consumption of neferine may have cancer-preventive and cancer-therapeutic benefit.
鉴定具有抗肿瘤活性的天然产物对于癌症的化学预防和治疗非常重要。在世界上的一些地方，人们将莲（Nelumbo nucifera）的胚胎作为饮料食用，认为其具有有益健康的作用。在本报告中，我们研究了莲胚胎中的主要生物碱成分小檗碱对人骨肉瘤细胞的作用及其潜在机制。我们发现小檗碱对人骨肉瘤细胞具有很强的生长抑制作用，但对非肿瘤性的人成骨细胞没有这种作用。小檗碱对人骨肉瘤细胞的抑制作用主要归因于细胞周期停滞在 G1 期。G1 期阻滞的诱导与 p21(WAF1/CIP1)的依赖性有关，但与 p53 或 RB（视网膜母细胞瘤相关蛋白）无关。小檗碱上调 p21 是由于 p21 蛋白半衰期的增加。我们检查了已知影响 p21 稳定性的四种激酶，发现小檗碱能激活 p38 MAPK 和 JNK。然而，只有 SB203580（p38 的抑制剂），而不是 SP600125（JNK 的抑制剂），能减弱小檗碱对 p21 的上调作用。此外，当用 RNA 干扰沉默 p38 时，小檗碱对 p21 的稳定作用被消除。最后，我们表明小檗碱处理导致 p21 在 Ser130 处的磷酸化增加，这依赖于 p38。我们的研究结果首次表明小檗碱具有直接的抗肿瘤作用，提示小檗碱的摄入可能具有预防和治疗癌症的益处。
