Sanguinarine cytotoxicity on mouse melanoma K1735-M2 cells-Nuclear vs. mitochondrial effects
Sanguinarine cytotoxicity on mouse melanoma K1735-M2 cells-Nuclear vs. mitochondrial effects
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DOI：
10.1016/j.bcp.2008.07.013
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发表时间：
2008-12-01
影响因子：
5.8
通讯作者：
Oliveira, Paulo J.
中科院分区：
文献类型：
--
作者：
Serafim, Teresa L.;Matos, Julio A. C.;Oliveira, Paulo J.
血根碱（SANG）是一种生物碱，被认为对各种人类肿瘤细胞系具有抗增殖活性。晚期恶性黑色素瘤对SANG的易感性尚无数据，尽管由于对常规化疗的耐药性，如果不能及时发现，这种疾病的预后非常差。本工作旨在研究细胞核和线粒体参与的促凋亡作用的SANG在侵袭性小鼠黑色素瘤细胞系。所获得的结果表明，SANG主要由细胞核积累，导致细胞增殖抑制和诱导细胞死亡，如通过亚G1峰的增加所证实的。在低浓度下，SANG诱导黑色素瘤细胞亚群中的线粒体去极化，其通常也显示出磷酸化组蛋白H2AX的强核标记。蛋白质印迹法显示p53的增加，但不是Bax蛋白，在全细胞提取物和线粒体组分。分离的肝线粒体组分显示，SANG影响线粒体呼吸链，并对线粒体钙负荷能力具有双重作用。我们认为，SANG能够诱导转移性黑色素瘤细胞凋亡。了解SANG的线粒体与核效应对于开发这种有前景的化合物用于临床治疗侵袭性黑色素瘤非常重要。(C)2008年爱思唯尔公司All rights reserved.
Sanguinarine (SANG) is an alkaloid recognized to have anti-proliferative activity against various human tumour cell lines. No data is available on the susceptibility of advanced malignant melanoma to SANG, although this disease has a very poor prognosis if not detected in time due to the resistance to conventional chemotherapy. The present work was designed to study the nuclear and mitochondrial involvement in the pro-apoptotic effect of SANG in an invasive mouse melanoma cell line. The results obtained show that SANG is primarily accumulated by the cell nuclei, causing inhibition of cell proliferation and inducing cell death, as confirmed by an increase in sub-G1 peaks. At low concentrations, SANG induces mitochondrial depolarization in a sub-population of melanoma cells, which also generally displayed strong nuclear labelling of phosphorylated histone H2AX. Western blotting revealed an increase in p53, but not Bax protein, in both whole-cell extracts and in mitochondrial fractions. isolated hepatic mitochondrial fractions revealed that SANG affects the mitochondrial respiratory chain, and has dual effects on mitochondrial calcium loading capacity. We suggest that SANG is able to induce apoptosis in metastatic melanoma cells. The knowledge of mitochondrial vs. nuclear effects of SANG is important in the development of this promising compound for clinical use against aggressive melanoma. (C) 2008 Elsevier Inc. All rights reserved.