Quiroga Adoración G, Cama Marta, Pajuelo-Lozano Natalia, Álvarez-Valdés Amparo, Sanchez Perez Isabel
Inorganic Chemistry Department, Universidad Autónoma de Madrid and IAdChem Universidad Autónoma de Madrid, Madrid 28049, Spain.
Biochemistry Department, Faculty of Medicine, Instituto de Investigaciones Biomédicas Alberto Sols. CSIC-UAM, Madrid 28029, Spain.
ACS Omega. 2019 Dec 3;4(26):21855-21861. doi: 10.1021/acsomega.9b02831. eCollection 2019 Dec 24.
We have selected a series of aliphatic amine platinum compounds bearing chloride and/or iodide as the leaving groups. The complexes' cytotoxicity and interaction with DNA indicated differences in the reactivity. Now, we are reporting on the analysis of their molecular mechanism of action on gastric cancer cells. Our data reveals differences between them. Chlorido drugs showed similar behavior to cisplatin; they both required p53 to induce apoptosis but only -ipa showed DNA damage requirement for apoptosis induction. On the contrary, and iodido induced cell death independent of p53 activity, and they induced cell death through Bid activation, so their toxicity could be enhanced in a combined treatment with novel Bcl-2 protein family inhibitors. We also report the structural features of the DNA adduct for one of the complexes by X-ray diffraction. These findings represent a step forward in the search for new platinum-derived agents more specific and effective in the treatment of cancer.
我们选择了一系列以氯和/或碘作为离去基团的脂肪族胺铂化合物。这些配合物的细胞毒性以及与DNA的相互作用表明了其反应活性存在差异。现在，我们报告它们对胃癌细胞作用的分子机制分析。我们的数据揭示了它们之间的差异。含氯药物表现出与顺铂相似的行为；它们都需要p53来诱导细胞凋亡，但只有-ipa显示出诱导细胞凋亡需要DNA损伤。相反，含碘药物诱导细胞死亡不依赖于p53活性，并且它们通过Bid激活来诱导细胞死亡，因此在与新型Bcl-2蛋白家族抑制剂联合治疗中其毒性可能会增强。我们还通过X射线衍射报告了其中一种配合物的DNA加合物的结构特征。这些发现代表了在寻找对癌症治疗更具特异性和有效性的新型铂类药物方面向前迈出的一步。
