Interfering in apoptosis and DNA repair of cancer cells to conquer cisplatin resistance by platinum(iv) prodrugs
Interfering in apoptosis and DNA repair of cancer cells to conquer cisplatin resistance by platinum(iv) prodrugs
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通过铂 (iv) 前药干扰癌细胞的凋亡和 DNA 修复以克服顺铂耐药性
DOI：
10.1039/d0sc00197j
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发表时间：
2020-04-21
期刊：
影响因子：
8.4
通讯作者：
Guo, Zijian
中科院分区：
文献类型：
--
作者：
Zhang, Shuren;Zhong, Xuanmeng;Guo, Zijian
细胞凋亡和DNA损伤修复的失调是顺铂耐药的两个主要机制。设计了两种抗癌Pt- iv前药，其分子式为[Pt(NH3)(2)Cl-2(L-1)(2)] （1,l -1 = 3-氯-苯并[b]噻吩-2-羧酸）和[Pt(NH3)(2)Cl-2(L-2)] （2,l -2 = 3-氯-6-甲基苯并[b]噻吩-2-羧酸），用于靶向髓细胞白血病-1 (Mcl-1)， Mcl-1是一种抑制细胞凋亡和促进DNA损伤修复的蛋白质。复合物1和2对多种癌症细胞系，特别是顺铂耐药的非小细胞肺癌细胞和卵巢癌细胞表现出高的细胞毒性。与顺铂相比，这两种复合物对顺铂耐药癌细胞的耐药因子也明显降低。1和2都能有效进入癌细胞，造成DNA损伤，同时下调Mcl-1，引起明显的凋亡反应。复合物2还下调DNA损伤修复蛋白RAD51和BRCA2，抑制RAD51病灶的形成，这被认为是同源重组的关键步骤和功能性生物标志物。1和2对小鼠的急性毒性低于顺铂，更重要的是，它们对裸鼠非小细胞肺癌生长的抑制作用比顺铂强得多。复合物1和2是首批针对mcl -1的Pt-IV前药，后者可同步抑制顺铂耐药癌细胞的凋亡和DNA修复相关蛋白。同时调控细胞凋亡和DNA修复途径的策略为克服顺铂耐药在抗癌化疗中的应用打开了一扇有希望的窗口，也是设计多效铂类抗癌药物的一个突破。
The dysregulation of apoptosis and DNA damage repair are two leading mechanisms of cisplatin resistance. Two anticancer Pt-IV prodrugs with the formulas [Pt(NH3)(2)Cl-2(L-1)(2)] (1, L-1 = 3-chloro-benzo[b]thiophene-2-carboxylic acid) and [Pt(NH3)(2)Cl-2(L-2)(2)] (2, L-2 = 3-chloro-6-methylbenzo[b]thiophene-2-carboxylic acid) were designed to target myeloid cell leukemia-1 (Mcl-1), a protein responsible for inhibiting apoptosis and promoting DNA damage repair. Complexes 1 and 2 exhibited high cytotoxicity against various cancer cell lines, especially cisplatin-resistant non-small-cell lung and ovarian cancer cells. The resistance factors of both complexes for cisplatin-resistant cancer cells also decreased markedly as compared with that of cisplatin. Both 1 and 2 could enter cancer cells effectively and cause DNA damage while simultaneously downregulating Mcl-1 to prompt a conspicuous apoptotic response. Complex 2 also downregulated the DNA damage repair proteins RAD51 and BRCA2 as well as inhibited the formation of RAD51 foci, which is regarded as a critical step and functional biomarker in homologous recombination. The acute toxicity of 1 and 2 to mice is lower than that of cisplatin, and more importantly, they show much stronger inhibition towards the growth of non-small-cell lung cancer in nude mice than cisplatin. Complexes 1 and 2 are the first Mcl-1-targeted Pt-IV prodrugs, and the latter could synchronously inhibit apoptosis and DNA repair related proteins in cisplatin-resistant cancer cells. The strategy of tuning both apoptosis and DNA repair pathways opens a promising window to overcoming resistance to cisplatin in anticancer chemotherapy, and is also a breakthrough in the design of multitalented platinum-based anticancer drugs.