Effective platinum(IV) prodrugs conjugated with lonidamine as a functional group working on the mitochondria
Effective platinum(IV) prodrugs conjugated with lonidamine as a functional group working on the mitochondria
复制标题
有效的铂 (IV) 前药与氯尼达明缀合作为作用于线粒体的功能基团
DOI：
10.1016/j.jinorgbio.2017.11.017
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发表时间：
2018-03-01
影响因子：
3.9
通讯作者：
Gou, Shaohua
中科院分区：
文献类型：
--
作者：
Chen, Hong;Chen, Feihong;Gou, Shaohua
铂类抗癌药物是肿瘤领域应用最广泛的抗癌化疗药物之一。在临床前研究中，Lonidamine （LND）可以通过作用于线粒体来提高人类肿瘤细胞对铂（II）类药物的反应。本文制备了五种与它们的增强剂LND偶联的铂（IV）前体药物，大多数靶配合物与它们的铂（II）前体相比具有更高的抗癌活性。值得注意的是，顺铂衍生的Pt(NH3)(2)(LND)Cl-3（复合物1）对LNCaP细胞的抗癌活性显著提高，并可能通过凋亡途径引发癌细胞死亡，细胞周期主要停留在S期。复合物1诱导LNCaP细胞凋亡与线粒体功能破坏和活性氧（ROS）积累密切相关。此外，它具有克服顺铂耐药的能力。进一步的研究表明，配合物1很容易被抗坏血酸还原释放其铂（II）前体和轴向配体。这些结果为铂缀合物及其增效剂的设计策略提供了依据，以提高其抗癌效果。
Platinum-based anticancer drugs are one of the most widely used anticancer chemotherapeutics in oncology. Lonidamine (LND) could increase the response of human tumor cells to platinum(II) drugs in preclinical studies by working on the mitochondria. Herein, five platinum(IV) prodrugs conjugated with their potentiator LND are prepared, and most of the target complexes achieve improved anticancer activities compared with their platinum (II) precursors. Notably, Pt(NH3)(2)(LND)Cl-3 (complex 1) derived from cisplatin achieve significantly improved anticancer activities against LNCaP cells and could trigger cancer cell death via an apoptotic pathway and the cell cycle arrest mainly at S phases. And the induction of apoptosis by complex 1 in LNCaP cells is closely associated with mitochondria] function disruption and reactive oxygen species (ROS) accumulation. Moreover, it is possessed of the ability to overcome cisplatin-resistance. Further research revealed that complex 1 could be easily reduced to release its platinum(II) precursor and axial ligand by ascorbic acid. All the results provid evidence to support the design strategy of conjugating platinum complexes with its potentiator to improve their anticancer effect.