The synergy between alkylating agents and ERCC1-XPF inhibitors is p53 dependent.

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY Fundamental & Clinical Pharmacology Pub Date : 2024-11-08 DOI:10.1111/fcp.13043

Gloria Ciniero, Tiago Marques Pedro, Charles Dumontet, Ahmed H Elmenoufy, Frederick G West, Michael Weinfeld, Francesco Gentile, Jack A Tuszynski, Emeline Cros-Perrial, Lars Petter Jordheim

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Abstract

Background: DNA repair plays a major role in maintaining genomic stability, thus limiting the transformation of normal cells into cancer cells. However, in cancer patients treated with DNA-targeting drugs, DNA repair can decrease efficacy by removing the damage generated by such molecules that is needed to induce pharmacological activity. Inhibiting DNA repair thus represents an interesting approach to potentiating the activity of chemotherapy in this setting.

Objectives: Here, we continue the characterization of an inhibitor of the interaction between Excision Repair Cross-Complementing Rrodent repair deficiency complementation group 1 (ERCC1) and Xeroderma Pigmentousum group F (XPF) (B9), two key proteins of nucleotide excision repair.

Methods: We used various cell lines and co-incubation studies for the determination of cell survival and DNA repair capacities.

Results: We show that it is synergistic with other platinum derivatives than previously described, and that synergy is lacking in cells not expressing ERCC1 or XPF. Finally, a series of experiments show that potentiation is observed only in cells expressing wild-type p53.

Conclusion: Our results confirm the mechanism of action of our ERCC1-XPF inhibitor and give important additional data on this approach to enhance the activity of already existing cancer drugs.

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烷化剂与 ERCC1-XPF 抑制剂之间的协同作用取决于 p53。

背景：DNA 修复在维持基因组稳定性方面发挥着重要作用，从而限制了正常细胞向癌细胞的转化。然而，在使用 DNA 靶向药物治疗的癌症患者中，DNA 修复可通过消除此类分子产生的损伤（诱导药理活性所需的损伤）而降低疗效。因此，抑制 DNA 修复是在这种情况下增强化疗活性的一种有趣方法：在此，我们继续研究核苷酸切除修复的两个关键蛋白--切除修复交叉互补Rrodent修复缺陷互补组1（ERCC1）和色素沉着病F组（XPF）（B9）之间相互作用的抑制剂的特性：方法：我们利用各种细胞系和共孵育研究来测定细胞存活和 DNA 修复能力：结果：我们发现，与之前描述的其他铂衍生物相比，它具有协同作用，而且在不表达 ERCC1 或 XPF 的细胞中缺乏协同作用。最后，一系列实验表明，只有在表达野生型 p53 的细胞中才能观察到增效作用：我们的研究结果证实了我们的 ERCC1-XPF 抑制剂的作用机制，并为这种增强现有抗癌药物活性的方法提供了重要的补充数据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Fundamental & Clinical Pharmacology 医学-药学

CiteScore

5.30

自引率

6.90%

发文量

111

审稿时长

6-12 weeks

期刊介绍： Fundamental & Clinical Pharmacology publishes reports describing important and novel developments in fundamental as well as clinical research relevant to drug therapy. Original articles, short communications and reviews are published on all aspects of experimental and clinical pharmacology including: Antimicrobial, Antiviral Agents Autonomic Pharmacology Cardiovascular Pharmacology Cellular Pharmacology Clinical Trials Endocrinopharmacology Gene Therapy Inflammation, Immunopharmacology Lipids, Atherosclerosis Liver and G-I Tract Pharmacology Metabolism, Pharmacokinetics Neuropharmacology Neuropsychopharmacology Oncopharmacology Pediatric Pharmacology Development Pharmacoeconomics Pharmacoepidemiology Pharmacogenetics, Pharmacogenomics Pharmacovigilance Pulmonary Pharmacology Receptors, Signal Transduction Renal Pharmacology Thrombosis and Hemostasis Toxicopharmacology Clinical research, including clinical studies and clinical trials, may cover disciplines such as pharmacokinetics, pharmacodynamics, pharmacovigilance, pharmacoepidemiology, pharmacogenomics and pharmacoeconomics. Basic research articles from fields such as physiology and molecular biology which contribute to an understanding of drug therapy are also welcomed.