Neferine, an alkaloid ingredient in lotus seed embryo, inhibits proliferation of human osteosarcoma cells by promoting p38 MAPK-mediated p21 stabilization.
ABSTRACT 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.
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ABSTRACT: Neferine is the major bisbenzylisoquinoline alkaloid isolated from the seed embryo of a traditional medicinal plant Nelumbo nucifera (Lotus). Epidemiological studies have revealed the therapeutic potential of lotus seed embryo. Although several mechanisms have been proposed, a clear anticancer action mechanism of neferine on lung cancer cells is still not known. Lung cancer is the most common cause of cancer death in the world, and the patients with advanced stage of nonsmall lung cancer require adjunct chemotherapy after surgical resection for the eradication of cancer cells. In this study, the effects of neferine were evaluated and characterized in A549 cells. Neferine induced apoptosis in a dose-dependent manner with the hypergeneration of reactive oxygen species, activation of MAPKs, lipid peroxidation, depletion of cellular antioxidant pool, loss of mitochondrial membrane potential, and intracellular calcium accumulation. Furthermore, neferine treatment leads to the inhibition of nuclear factor kappaB and Bcl2, upregulation of Bax and Bad, release of cytochrome C, activation of caspase cascade, and DNA fragmentation. In addition, neferine could induce p53 and its effector protein p21 and downregulation of cell cycle regulatory protein cyclin D1 thereby inducing G1 cell cycle arrest. These results suggest a novel function of neferine as an apoptosis inducer in lung cancer cells. © 2013 BioFactors, 2013.BioFactors 08/2013; · 3.09 Impact Factor
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ABSTRACT: Lotus plumule, the dried young cotyledon and radicle of the Nelumbo nucifera Gaertn. (Fam. Nymphaeaceae) ripe seed, is a famous Traditional Chinese Medicine to remove heat from the heart, anchor the mind, improve seminal emission, and arrest bleeding for centuries in China. Liensinine and its analogs neferine and isoliensinine are the major active components in lotus plumule. To investigate the association of liensinine, neferine, and isoliensinine with efflux transporters. Caco-2, MDCK, MDCK-MDR1, and MDCK-MRP2 were used as cell models for the transcellular transport and accumulation studies. The results obtained in Caco-2 cells suggested that P-glycoprotein (P-gp) might be involved in transcellular transport. Cellular accumulation and transport experiments were further performed in MDCK-MDR1 cells. GF120918 and cyclosporine A were found to completely inhibit the efflux, and the net efflux ratios of these alkaloids exhibited saturation over the concentration range. No significant differences in liensinine accumulation and transport were observed between MDCK and MDCK-MRP2 cells. These results demonstrated that liensinine, neferine, and isoliensinine are substrates of P-gp, whereas MRP2 is not involved in the transport process, suggesting that P-gp might be responsible for the absorption and distribution of the 3 alkaloids.Journal of ethnopharmacology 09/2013; · 2.32 Impact Factor
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ABSTRACT: Diabetes mellitus has been identified as a major risk factor for cardiovascular diseases. High glucose-induced endothelial dysfunction and apoptosis is an important pathological feature of diabetic vasculopathy. Neferine, an alkaloid ingredient in lotus seed embryo has many biological actions such as anticancer and antioxidant. But little is known about whether Neferine protects endothelial cells against high glucose-induced oxidative stress and apoptosis. The present study was conducted to investigate the preventive effects of Neferine on hyperglycemia-induced injury of human umbilical vein endothelial cells (HUVECs). Our study showed that Neferine pretreatment effectively suppressed high glucose-induced HUVECs apoptosis. Also, Neferine pretreatment inhibited the augment of reactive oxygen species (ROS) in high glucose-treated HUVECs. The changes of SOD and MDA level in high glucose-treated HUVECs were also prevented by Neferine. Further study showed that Neferine did not affect the phosphorylation of JNK and p38 in high glucose-treated HUVECs. Interestingly, Neferine markedly inhibited high glucose-induced activation of PI3K/Akt pathway in HUVECs. High glucose-induced activation of NF-κB signal was also obviously suppressed by Neferine pretreatment. Collectively, we found that Neferine inhibited high glucose-induced endothelial apoptosis via blocking ROS/Akt/NF-κB pathway, which provides the evidence for using Neferine to treat diabetic vasculopathy.Endocrine 03/2014; · 1.42 Impact Factor