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A Pt(IV)-based mononitro-naphthalimide conjugate with minimized side-effects targeting DNA damage response via a dual-DNA-damage approach to overcome cisplatin resistance.
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2020-06-12 , DOI: 10.1016/j.bioorg.2020.104011
Yingguang Li 1 , Kexin Yue 1 , Linrong Li 1 , Jie Niu 1 , Hanfang Liu 1 , Jing Ma 1 , Songqiang Xie 1
Affiliation  

Platinum(Pt)(II) drugs and new Pt(IV) agents behave the dysregulation of apoptosis as the result of DNA damage repair and thus, are less effective in the treatment of resistant tumors. Herein, mononitro-naphthalimide Pt(IV) complex 10b with minimized side-effects was reported targeting DNA damage response via a dual-DNA-damage approach to overcome cisplatin resistance. 10b displayed remarkably evaluated antitumor (70.10%) activities in vivo compared to that of cisplatin (52.88%). The highest fold increase (FI) (5.08) for A549cisR cells and the lowest (0.72) for A549 indicated 10b preferentially accumulated in resistant cell lines. The possible molecular mechanism indicates that 10b targets resistant cells in a totally different way from the existing Pt drugs. The cell accumulation and the Pt levels in genomic DNA from 10b is almost 5 folds higher than that of cisplatin and oxaliplatin, indicating the naphthalimide moiety in 10b exhibits preferentially DNA damage. Using 5′-dGMP as a DNA model, the DNA-binding properties of 10b (1 mM) with 5′-dGMP (3 mM) in the presence of ascorbic acid (5 mM) deduced that 10b was generated by the combination of cisplatin with 5′-dGMP after reduction by ascorbic acid. Moreover, 10b promoted the expression of p53 gene and protein more effectively than cisplatin, leading to the increased anticancer activity. The up-regulated γH2A.X and down-regulated RAD51 indicates that 10b not only induced severe DNA damage but also inhibited the DNA damage repair, thus resulting in its higher cytotoxicity in comparison to that of cisplatin. Their preferential accumulation in cancer cells (SMMC-7721) compared to the matched normal cells (HL-7702 cells) demonstrated that they were potentially safe for clinical therapeutic use. In addition, the higher therapeutic indices of 10b for 4T1 cells in vivo indicated that naphthalimide-Pt(IV) conjugates behaved a vital function in the treatment of breast cancer. For the first time, our study implies a significant strategy for Pt drugs to treat resistance cancer targeting DNA damage repair via dual DNA damage mechanism in a totally new field.



中文翻译:

一种基于Pt(IV)的单硝基-萘二甲酰亚胺共轭物,可通过双重DNA损伤方法克服顺铂耐药性,从而将针对DNA损伤反应的副作用降至最低。

铂(Pt)(II)药物和新的Pt(IV)药物由于DNA损伤修复而导致细胞凋亡失调,因此在抗药性肿瘤的治疗中效果较差。在此,据报道,具有副作用最小的单硝基萘二甲酰亚胺Pt(IV)复合物10b通过双重DNA损伤方法克服顺铂耐药性而靶向DNA损伤反应。与顺铂(52.88%)相比,图10b显示了显着评估的体内抗肿瘤活性(70.10 %)。A549cisR细胞的最高倍数增加(FI)(5.08),而A549最低的(0.72)表明10b优先积累在抗性细胞系中。可能的分子机理表明10b以与现有Pt药物完全不同的方式靶向耐药细胞。来自10b的基因组DNA中的细胞蓄积和Pt水平几乎是顺铂和奥沙利铂的5倍,这表明10b中的萘二甲酰亚胺部分优先显示DNA损伤。使用5'-dGMP作为DNA模型,在抗坏血酸(5 mM)存在下10b(1 mM)与5'-dGMP(3 mM)的DNA结合特性推论出顺铂联合产生了10b用抗坏血酸还原后的5'-dGMP。而且10b比顺铂更有效地促进了p53基因和蛋白质的表达,从而提高了抗癌活性。γH2A.X的上调和RAD51的下调表明10b不仅引起严重的DNA损伤,而且抑制DNA损伤修复,因此与顺铂相比具有更高的细胞毒性。与匹配的正常细胞(HL-7702细胞)相比,它们在癌细胞(SMMC-7721)中的优先积累表明,它们对于临床治疗用途具有潜在的安全性。此外,体内4T1细胞的治疗指数更高,为10b指出萘二甲酰亚胺-Pt(IV)缀合物在乳腺癌的治疗中起着至关重要的作用。首次,我们的研究暗示了Pt药物在全新领域中通过双重DNA损伤机制治疗靶向DNA损伤修复的耐药性癌症的重要策略。

更新日期:2020-06-27
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