Effective tumor cell death by σ-2 receptor ligand siramesine involves lysosomal leakage and oxidative stress
Effective tumor cell death by σ-2 receptor ligand siramesine involves lysosomal leakage and oxidative stress
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DOI：
10.1158/0008-5472.can-05-0269
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发表时间：
2005-10-01
期刊：
影响因子：
11.2
通讯作者：
Jäättelä, M
中科院分区：
文献类型：
--
作者：
Ostenfeld, MS;Fehrenbacher, N;Jäättelä, M
对经典的caspase介导的细胞凋亡的获得性抵抗是人类癌症治疗中常见的问题。在这里，我们证明了西拉美辛，一种新的Sigma-2受体配体，有效地诱导了不同来源的永生化和转化细胞中caspase非依赖性的程序性细胞死亡。西拉美辛处理的肿瘤细胞显示出更高水平的活性氧，溶酶体膜通透性，染色质凝集，细胞收缩和脱落。脂类抗氧化剂(α-生育酚和伽马-生育酚)，而不是其他受试抗氧化剂(丁基羟基苯甲酚或N-乙酰半胱氨酸)，有效地抑制了西拉美辛诱导的形态变化和细胞死亡。组织蛋白酶B抑制剂(CA-074-Me和R-2525)具有类似的保护作用，但不那么明显，而异位表达抗凋亡蛋白Bcl2、缺乏野生型p53以及caspase的药理抑制剂(zVAD-fmk、DEVD-CHO和LeHD-CHO)、钙蛋白酶(PD150606)和丝氨酸蛋白酶(N-对甲苯磺酰-L-苯丙氨氯甲基酮和培法布洛克)不能保护细胞免受西拉姆诱导的死亡。重要的是，用活化的c-src或v-Ha-ras癌基因转化小鼠胚胎成纤维细胞，可以使它们对西拉美辛诱导的细胞毒性非常敏感。此外，邮政总局。在原位乳腺癌和S.C.中，给予耐受性良好的西拉美辛有显著的抗肿瘤作用。小鼠纤维肉瘤模型的建立。这些结果表明西拉美辛是一种很有前途的新药，用于治疗对传统疗法耐药的肿瘤。
Acquired resistance to classic caspase-mediated apoptosis is a common problem for the treatment of human cancer. Here, we show that siramesine, a novel sigma-2 receptor ligand, effectively induces caspase-independent programmed cell death in immortalized and transformed cells of various origins. Siramesine-treated tumor cells displayed increased levels of reactive oxygen species, lysosomal membrane permeabilization, chromatin condensation, and shrinkage and detachment of cells. Lipid antioxidants (alpha-tocopherol and gamma-tocopherol), but not other tested antioxidants (butylated hydroxyanisol or N-acetyl cysteine), effectively inhibited siramesine-induced morphologic changes and cell death. Cathepsin B inhibitors (CA-074-Me and R-2525) conferred similar, but less pronounced protection, whereas ectopic expression of antiapoptotic protein Bcl-2, lack of wild-type p53 as well as pharmacologic inhibitors of caspases (zVAD-fmk, DEVD-CHO, and LEHD-CHO), calpains (PD150606), and serine proteases (N-tosyl-L-phenylaianine chloromethyl ketone and pefabloc) failed to protect cells against siramesme-induced death. Importantly, transformation of murine embryonic fibroblasts with activated c-src or v-Ha-ras oncogenes greatly sensitized them to siramesine-induced cytotoxicity. Furthermore, p.o. administration of well-tolerated doses of siramesine had a significant antitumorigenic effect in orthotopic breast cancer and s.c. fibrosarcoma models in mice. These results present siramesine as a promising new drug for the treatment of tumors resistant to traditional therapies.