Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; JiangsuProvince Hi-Tech Key Laboratory for Bio-medical Research, SoutheastUniversity, Nanjing 211189, China.
Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; JiangsuProvince Hi-Tech Key Laboratory for Bio-medical Research, SoutheastUniversity, Nanjing 211189, China.
J Inorg Biochem. 2018 Mar;180:119-128. doi: 10.1016/j.jinorgbio.2017.11.017. Epub 2017 Nov 21.
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(NH)(LND)Cl (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 mitochondrial 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.
铂类抗癌药物是肿瘤学中最广泛使用的抗癌化疗药物之一。在临床前研究中，劳尼定（LND）通过作用于线粒体，可增加人肿瘤细胞对铂（II）类药物的反应。在此，制备了五种与增效剂 LND 偶联的铂（IV）前药，与铂（II）前体相比，大多数靶复合物的抗癌活性均得到提高。值得注意的是，源自顺铂的 Pt(NH)(LND)Cl（复合物 1）对 LNCaP 细胞表现出显著提高的抗癌活性，并可通过凋亡途径和主要在 S 期的细胞周期阻滞诱导癌细胞死亡。复合物 1 在 LNCaP 细胞中诱导的凋亡与线粒体功能障碍和活性氧（ROS）积累密切相关。此外，它还具有克服顺铂耐药的能力。进一步的研究表明，复合物 1 可以很容易地被抗坏血酸还原，释放其铂（II）前体和轴向配体。所有结果都为支持用其增效剂偶联铂类复合物以提高其抗癌效果的设计策略提供了证据。
