Doxorubicin (DOX) is a widely used classical broad-spectrum anticancer drug. The major mechanism of DOX-mediated anticancer activity at clinically relevant concentrations is believed to be via DNA double-strand breaks due to topoisomerase IIα. However, other mechanisms by which DOX causes cytotoxicity have been proposed, including formaldehyde-dependent virtual interstrand cross-linking (ICL) formation. In this study, a method was established whereby cytotoxicity caused by virtual ICL derived from DOX is turned on and off using a cell culture system. Using this strategy, DOX-mediated cytotoxicity in Fanconi anemia group gene (FANC)/breast cancer susceptibility gene (BRCA)-deficient cells increased up to 70-fold compared to that in cells proficient in DNA repair pathways by increasing intracellular formaldehyde (FA) concentration. This approach also demonstrated that cytotoxicity introduced by DOX-mediated FA-dependent virtual ICL is completely independent of the toxicity induced by topoisomerase II inhibition at the cellular level. The potential of dual-targeting by DOX treatment was verified using an acid-specific FA donor. Overall, anticancer therapy targeting tumors deficient in the FANC/BRCA pathway may be possible by minimizing DOX-induced toxicity in normal cells.

中文翻译：

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通过调节细胞甲醛浓度在 FANC/BRCA 缺陷肿瘤中进行潜在的阿霉素介导的双靶向化疗。

多柔比星（DOX）是一种广泛使用的经典广谱抗癌药物。在临床相关浓度下，DOX 介导的抗癌活性的主要机制被认为是通过拓扑异构酶 IIα 引起的 DNA 双链断裂。然而，已经提出了 DOX 引起细胞毒性的其他机制，包括甲醛依赖性虚拟链间交联 (ICL) 的形成。在这项研究中，建立了一种方法，即使用细胞培养系统打开和关闭由来自 DOX 的虚拟 ICL 引起的细胞毒性。使用这种策略，DOX 介导的范可尼贫血组基因 ( FANC )/乳腺癌易感基因 ( BRCA ) 中的细胞毒性)-缺陷细胞通过增加细胞内甲醛 (FA) 浓度与精通 DNA 修复途径的细胞相比增加了 70 倍。这种方法还表明，由 DOX 介导的 FA 依赖性虚拟 ICL 引入的细胞毒性完全独立于细胞水平的拓扑异构酶 II 抑制诱导的毒性。使用酸特异性 FA 供体验证了 DOX 处理双重靶向的潜力。总体而言，通过最大限度地减少 DOX 诱导的正常细胞毒性，靶向 FANC/BRCA 通路缺陷肿瘤的抗癌治疗可能成为可能。