A cyclopalladated complex interacts with mitochondrial membrane thiol-groups and induces the apoptotic intrinsic pathway in murine and cisplatin-resistant human tumor cells.
A cyclopalladated complex interacts with mitochondrial membrane thiol-groups and induces the apoptotic intrinsic pathway in murine and cisplatin-resistant human tumor cells.
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环胶的复合物与线粒体膜硫醇基团相互作用，并诱导鼠和抗顺铂耐药的人肿瘤细胞中的凋亡固有途径。
DOI：
10.1186/1471-2407-11-296
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发表时间：
2011-07-14
期刊：
影响因子：
3.8
通讯作者：
Rodrigues EG
中科院分区：
文献类型：
--
作者：
Serrano FA;Matsuo AL;Monteforte PT;Bechara A;Smaili SS;Santana DP;Rodrigues T;Pereira FV;Silva LS;Machado J Jr;Santos EL;Pesquero JB;Martins RM;Travassos LR;Caires AC;Rodrigues EG
癌症转移性病变的全身治疗是困难的，并且通常表现出较差的临床反应。顺铂的结构类似物是最广泛使用的合成金属配合物，其显示毒副作用和肿瘤细胞抗性。最近，正在研究具有增加的稳定性的钯络合物以克服这些限制，并且命名为C7 a的双膦环钯化络合物{Pd 2 [S（-）C2，N-dmpa]2（μ-dppe）Cl 2}有效地控制同基因小鼠中B16 F10-Nex 2鼠黑素瘤的皮下发展。目前，我们研究了C7 a对黑色素瘤细胞的杀伤机制，并进行了临床前研究。在存在/不存在DTT的情况下用C7 a体外处理B16 F10-Nex 2细胞，并评价与凋亡诱导相关的几个参数。进行临床前研究，用B16 F10-Nex 2细胞内接种小鼠，用C7 a腹膜内处理，并对肺转移结节进行计数。还在体外用C7 a处理的人肿瘤细胞系中测定了细胞毒性作用和呼吸代谢。环钯络合物与线粒体膜蛋白上的巯基相互作用，引起线粒体膜电位的耗散，并诱导Bax从细胞质易位到线粒体，与线粒体示踪剂共定位。C7 a还诱导主要来自细胞内室的胞质钙浓度的增加，以及ATP水平的显著降低。效应半胱天冬酶，染色质凝聚和DNA降解的激活，表明C7 a激活小鼠黑色素瘤细胞的凋亡内在途径。在临床前研究中，C7 a复合物在体外保护鼠转移性黑色素瘤，并诱导几种人类肿瘤细胞系（包括顺铂耐药细胞）死亡。C7 a在人肿瘤细胞中也诱导了C7 a依赖的细胞死亡。环钯化C7 a复合物是一种有效的抗癌化疗化合物，针对原发性和转移性小鼠和人类肿瘤，包括顺铂耐药细胞，通过内在途径诱导细胞凋亡。
Systemic therapy for cancer metastatic lesions is difficult and generally renders a poor clinical response. Structural analogs of cisplatin, the most widely used synthetic metal complexes, show toxic side-effects and tumor cell resistance. Recently, palladium complexes with increased stability are being investigated to circumvent these limitations, and a biphosphinic cyclopalladated complex {Pd2 [S(-)C2, N-dmpa]2 (μ-dppe)Cl2} named C7a efficiently controls the subcutaneous development of B16F10-Nex2 murine melanoma in syngeneic mice. Presently, we investigated the melanoma cell killing mechanism induced by C7a, and extended preclinical studies. B16F10-Nex2 cells were treated in vitro with C7a in the presence/absence of DTT, and several parameters related to apoptosis induction were evaluated. Preclinical studies were performed, and mice were endovenously inoculated with B16F10-Nex2 cells, intraperitoneally treated with C7a, and lung metastatic nodules were counted. The cytotoxic effects and the respiratory metabolism were also determined in human tumor cell lines treated in vitro with C7a. Cyclopalladated complex interacts with thiol groups on the mitochondrial membrane proteins, causes dissipation of the mitochondrial membrane potential, and induces Bax translocation from the cytosol to mitochondria, colocalizing with a mitochondrial tracker. C7a also induced an increase in cytosolic calcium concentration, mainly from intracellular compartments, and a significant decrease in the ATP levels. Activation of effector caspases, chromatin condensation and DNA degradation, suggested that C7a activates the apoptotic intrinsic pathway in murine melanoma cells. In the preclinical studies, the C7a complex protected against murine metastatic melanoma and induced death in several human tumor cell lineages in vitro, including cisplatin-resistant ones. The mitochondria-dependent cell death was also induced by C7a in human tumor cells. The cyclopalladated C7a complex is an effective chemotherapeutic anticancer compound against primary and metastatic murine and human tumors, including cisplatin-resistant cells, inducing apoptotic cell death via the intrinsic pathway.
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影响因子：
3.9
作者：
HIGGINS, JD;NEELY, L;FRICKER, S
通讯作者：
FRICKER, S
影响因子：
3.7
作者：
de Graaf, AO;van den Heuvel, LP;Jansen, JH
通讯作者：
Jansen, JH
影响因子：
2.2
作者：
Freitas, ZFO;Rodrigues, EG;Travassos, LR
通讯作者：
Travassos, LR
影响因子：
5.8
作者：
BINKS, SP;DOBROTA, M
通讯作者：
DOBROTA, M
影响因子：
4.8
作者：
Halestrap, AP;Woodfield, KY;Connern, CP
通讯作者：
Connern, CP