N-methylhemeanthidine chloride, a novel Amaryllidaceae alkaloid, inhibits pancreatic cancer cell proliferation via down-regulating AKT activation
N-methylhemeanthidine chloride, a novel Amaryllidaceae alkaloid, inhibits pancreatic cancer cell proliferation via down-regulating AKT activation
复制标题
N-甲基半氮啶氯化物是一种新型石蒜科生物碱，通过下调 AKT 激活来抑制胰腺癌细胞增殖
DOI：
10.1016/j.taap.2014.08.009
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发表时间：
2014-11-01
影响因子：
3.8
通讯作者：
Liu, Hudan
中科院分区：
文献类型：
--
作者：
Guo, Guoli;Yao, Guangmin;Liu, Hudan
我们以前报道的分离一种新的石蒜科生物碱，N-甲基hemeanthidine氯化物（NMHC），从Zephyranthes candida，表现出强大的细胞毒性谱的肿瘤细胞。然而，其作用机制仍不清楚。使用来自人胰腺癌的多个细胞系，最致命和难治的人类恶性肿瘤之一，我们进一步研究了NMHC介导的细胞毒性，发现它在胰腺癌细胞中诱导剧烈的细胞毒性，而对非癌细胞系的影响不显著。NMHC介导的生长抑制比一线化疗药物吉西他滨更严重，导致细胞周期停滞、凋亡性死亡和糖酵解减少。NMHC通过下调AKT的激活发挥作用，而激活的AKT的异位表达可缓解生长抑制。因此，在胰腺癌异种移植模型中注射NMHC显示了体内抗肿瘤作用。移植的肿瘤细胞在处理后经历AKT衰减和凋亡性死亡。因此，我们在这里证明AKT抑制可能是NMHC在体外和体内降低肿瘤细胞存活率的机制之一。因此，我们的数据表明，NMHC作为一种有效的化疗药物对胰腺癌有很大的希望，并揭示了新的光从天然产物中获得这些药物对治疗目的。(C)2014爱思唯尔公司All rights reserved.
We previously reported the isolation of a novel Amaryllidaceae alkaloid, N-methylhemeanthidine chloride (NMHC), from Zephyranthes candida, which exhibits potent cytotoxicity in a spectrum of tumor cells. However, the mechanism of action remains unclear. Using multiple cell lines derived from human pancreatic cancer, one of the most mortal and refractory human malignancies, we further studied the NMHC-mediated cytotoxicity and found that it induced drastic cytotoxicity in pancreatic cancer cells whereas an insignificant effect on a noncancerous cell line. The NMHC-mediated growth inhibition was more severe than the first-line chemotherapeutic agent gemcitabine, leading to cell cycle arrest, apoptotic death and decreased glycolysis. NMHC exerted its function through down-regulating AKT activation, and the ectopic expression of activated AKT rescued the growth inhibition. Consistently, NMHC injections in a pancreatic cancer xenograft model manifested the antitumor effect in vivo. Engrafted tumor cells underwent AKT attenuation and apoptotic death upon treatments. As such, we here demonstrate the AKT inhibition may be one of the mechanisms by which NMHC decreases tumor cell survival rate in vitro and in vivo. Our data thereby suggest that NMHC holds great promise as a potent chemotherapeutic agent against pancreatic cancer and sheds new light on obtaining such agents from natural products toward therapeutic purposes. (C) 2014 Elsevier Inc. All rights reserved.