期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 705, 期 1-3, 页码 109-118出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2013.02.035
关键词
Sanguinarine; Human melanoma cells; Oxidative stress; Mitochondria; Endoplasmic reticulum; Caspase activation
资金
- Fundacao para a Ciencia e a Tecnologia (FCT) [PTDC/QUI-QUI/101409/2008, PEst-C/SAU/LA0001/2011]
- Feder/Compete/National Funds
- Ministerio de Economia y Competitividad of Spain [SAF2008-02251, SAF2011-30518]
- Red Tematica de Investigacion Cooperativa en Cancer
- Instituto de Salud Carlos III
- Fondo Europeo de Desarrollo Regional of the European Union [RD06/0020/1037, RD12/0036/0065]
- Fondo de Investigacion Sanitaria
- European Commission [PS09/01915]
- Junta de Castilla y Leon [CSI052A11-2, CSI221A12-2]
- Portuguese FCT [SFRH/BD/32943/2006]
- Spanish Ministerio de Ciencia e Innovacion
- Fundação para a Ciência e a Tecnologia [SFRH/BD/32943/2006, PTDC/QUI-QUI/101409/2008] Funding Source: FCT
Sanguinarine is a natural isoquinoline alkaloid derived from the root of Sanguinaria canadensis and from other poppy fumaria species, and is known to have a broad spectrum of pharmacological properties. Here we have found that sanguinarine, at low micromolar concentrations, showed a remarkably rapid killing activity against human melanoma cells. Time-lapse videomicroscopy showed rapid morphological changes compatible with an apoptotic cell death, which was further supported by biochemical markers, including caspase activation, poly(ADP-ribose) polymerase (PAPP) cleavage and DNA breakdown. Pan-caspase inhibition blocked sanguinarine-induced cell death. Sanguinarine treatment also induced an increase in intracellular calcium concentration, which was inhibited by dantrolene, and promoted cleavage of BAP-31, thus suggesting a putative role for Ca2+ release from endoplasmic reticulum and a cross-talk between endoplasmic reticulum and mitochondria in the anti-melanoma action of sanguinarine. Sanguinarine disrupted the mitochondrial transmembrane potential (Delta psi(m)), released cytochrome c and Smac/DIABLO from mitochondria to cytosol, and induced oxidative stress. Overexpression of Bcl-X-L by gene transfer did not prevent sanguinarine-mediated cell death, oxidative stress or release of mitochondrial apoptogenic proteins. However, preincubation with N-acetyl-L-cysteine (NAC) prevented sanguinarine-induced oxidative stress, PARP cleavage, release of apoptogenic mitochondrial proteins, and cell death. Pretreatment with glutathione (GSH) also inhibited the anti-melanoma activity of sanguinarine. Thus, pretreatment with the thiol antioxidants NAC and GSH abrogated the killing activity of sanguinarine. Taking together, our data indicate that sanguinarine is a very rapid inducer of human melanoma caspase-dependent cell death that is mediated by oxidative stress. (C) 2013 Elsevier B.V. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据