Antiproliferative and apoptotic effects of two new gold(III) methylsarcosinedithiocarbamate derivatives on human acute myeloid leukemia cells in vitro
Antiproliferative and apoptotic effects of two new gold(III) methylsarcosinedithiocarbamate derivatives on human acute myeloid leukemia cells in vitro
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DOI：
10.1097/cad.0b013e328011ae98
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发表时间：
2007-03-01
影响因子：
2.3
通讯作者：
Fregona, Dolores
中科院分区：
文献类型：
--
作者：
Aldinucci, Donatella;Lorenzon, Debora;Fregona, Dolores
[Au（MSDT）Cl-2]（二氯[甲基N-（二硫代羧基-kS，kS）-N-甲基甘氨酸]金（III）和[Au（MSDT）Br-2]（二溴[甲基N-（二硫代羧基-kS，kS）-N-甲基甘氨酸]金（III））二硫代氨基甲酸酯衍生物是两种新合成的甲基肌氨酸二硫代氨基甲酸酯的金（III）衍生物，其含有能够强烈结合金属中心的硫螯合配体，从而防止与含硫酶的相互作用;事实上，这些反应被认为是铂（II）基药物诱导的肾毒性的原因。它们的活性已与众所周知的铂类抗癌剂顺铂在代表不同法国-美国-英国亚型的急性髓性白血病细胞系和费城阳性细胞系K562上进行了比较。两种化合物均以剂量依赖性方式抑制甲基纤维素中的菌落形成，其ID 50值约为参比药物的1/10。经过短暂的曝光（18小时），我们的化合物，但不是顺铂，能够：下调抗凋亡分子Bcl-2，上调促凋亡分子Bax和诱导细胞凋亡，确定了一个强大的诱导APO2.7和磷脂酰丝氨酸曝光。最后，经过72小时的曝光，这两个金（III）二硫代氨基甲酸酯衍生物确定适度的细胞周期的修改，但诱导DNA片段在所有骨髓细胞系测试。总之，我们的研究结果表明，这些新的金（III）二硫代氨基甲酸酯衍生物可能代表新的潜在活性药物的管理髓性白血病，能够结合联合收割机细胞生长抑制和细胞凋亡的活性，降低肾毒性。
[Au(MSDT)Cl-2] (dichloro[methyl N-(dithiocarboxy-kS,kS)-N-methylglicinato]gold(III) and [Au(MSDT)Br-2] (dibromo[methyl N-(dithiocarboxy-kS,kS)-N-methylglicinato]gold(ill)) gold(III) dithiocarbamate derivatives are two newly synthesized gold(III) derivatives of methylsarcosinedithiocarbamate, containing a sulfur chelating ligand that is able to bind the metal center strongly, so preventing interactions with sulfur-containing enzymes; in fact these reactions are believed to be responsible for the nephrotoxicity induced by the platinum(II)-based drugs. Their activity has been compared with the well-known platinum-based anticancer agent cisplatin on a panel of acute myelogenous leukemia cell lines representing different French-American-British subtypes and in the Philadelphia-positive cell line K562. Both compounds suppressed, in a dose-dependent manner, colony formation in methylcellulose with ID50 values of about 10-fold lower than that of the reference drug. After a short exposure (18 h), our compounds, but not cisplatin, were able to: downregulate the antiapoptotic molecule Bcl-2, upregulate the proapoptotic molecule Bax and induce apoptosis, as determined by a strong induction of APO2.7 and phosphatidylserine exposure. Finally, after a 72-h exposure, both gold(III) dithiocarbamate derivatives determined modest cell cycle modifications, but induced DNA fragmentation in all myeloid cell lines tested. Altogether, our results indicate that these new gold(III) dithiocarbamate derivatives might represent novel potentially active drugs for the management of myeloid leukemia, able to combine cytostatic and apoptotic activity with reduced nephrotoxicity.