Salinomycin induces calpain and cytochrome c-mediated neuronal cell death.
Salinomycin induces calpain and cytochrome c-mediated neuronal cell death.
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DOI：
10.1038/cddis.2011.46
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发表时间：
2011-06-02
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
盐霉素是一种具有离子载体性质的聚醚类抗生素，通常用作抗球虫药物，并已显示在体外和体内消除癌症干细胞（CSC）方面非常有效。盐霉素潜在临床应用的一个重要警告是其显著的神经和肌肉毒性。在本研究中，我们表明，盐霉素的浓度对CSC有效发挥深刻的毒性对背根神经节以及雪旺细胞。这种毒性作用是由升高的胞质Na+浓度介导的，这反过来又通过质膜以及线粒体中的Na+/Ca 2+交换剂（NCXs）引起胞质Ca 2+的增加。升高的Ca 2+然后导致钙蛋白酶激活，其触发涉及半胱天冬酶12、9和3的半胱天冬酶依赖性细胞凋亡。此外，从去极化线粒体释放的细胞色素c直接激活半胱天冬酶9。钙蛋白酶和线粒体NCX的组合抑制导致细胞毒性显著降低，并且与半胱天冬酶3抑制相当。这些发现提高了我们对周围神经病变发病机制的理解，对于制定预防盐霉素引起的神经毒性副作用的策略具有重要意义。
Salinomycin is a polyether antibiotic with properties of an ionophore, which is commonly used as cocciodiostatic drug and has been shown to be highly effective in the elimination of cancer stem cells (CSCs) both in vitro and in vivo. One important caveat for the potential clinical application of salinomycin is its marked neural and muscular toxicity. In the present study we show that salinomycin in concentrations effective against CSCs exerts profound toxicity towards both dorsal root ganglia as well as Schwann cells. This toxic effect is mediated by elevated cytosolic Na+ concentrations, which in turn cause an increase of cytosolic Ca2+ by means of Na+/Ca2+ exchangers (NCXs) in the plasma membrane as well as the mitochondria. Elevated Ca2+ then leads to calpain activation, which triggers caspase-dependent apoptosis involving caspases 12, 9 and 3. In addition, cytochrome c released from depolarized mitochondria directly activates caspase 9. Combined inhibition of calpain and the mitochondrial NCXs resulted in significantly decreased cytotoxicity and was comparable to caspase 3 inhibition. These findings improve our understanding of mechanisms involved in the pathogenesis of peripheral neuropathy and are important to devise strategies for the prevention of neurotoxic side effects induced by salinomycin.
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影响因子：
7.3
作者：
Kim, Ju-Hwa;Chae, Minji;Yoon, Sungpil
通讯作者：
Yoon, Sungpil
影响因子：
--
作者：
Seyb KI;Schuman ER;Ni J;Huang MM;Michaelis ML;Glicksman MA
通讯作者：
Glicksman MA
影响因子：
3.2
作者：
Hoornstra, D;Andersson, MA;Salkinoja-Salonen, MS
通讯作者：
Salkinoja-Salonen, MS
影响因子：
64.5
作者：
Gupta PB;Onder TT;Jiang G;Tao K;Kuperwasser C;Weinberg RA;Lander ES
通讯作者：
Lander ES
DOI：
10.1016/0006-291x(75)90490-8
发表时间：
1975-01-01
影响因子：
3.1
作者：
MITANI, M;YAMANISHI, T;MIYAZAKI, Y
通讯作者：
MIYAZAKI, Y