Targeting ATR Kinase as a Strategy for Canine Lymphoma and Leukaemia Treatment.

IF 2.3 2区 农林科学 Q1 VETERINARY SCIENCES Veterinary and comparative oncology Pub Date : 2024-12-01 Epub Date: 2024-09-20 DOI:10.1111/vco.13014
Marta Henklewska, Aleksandra Pawlak, Bożena Obmińska-Mrukowicz
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Abstract

Ataxia telangiectasia and Rad3-related (ATR) kinase is one of the main regulators of cell response to DNA damage and replication stress. Effectiveness of ATR targeting in human cancers has been confirmed in preclinical studies and ATR inhibitors are currently developed clinically in human oncology. In the presented study, we tested the anticancer efficacy of ATR inhibitor berzosertib in an in vitro model of canine haematopoietic cancers. Using MTT assay and flow cytometry, we assessed the cytotoxicity of berzosertib in four established canine lymphoma and leukaemia cell lines and compared it with its activity against noncancerous canine cells. Further, we estimated the level of apoptosis in berzosertib-treated cells via flow cytometry and assessed H2AX phosphorylation as a marker of DNA damage using western blot technique. In flow-cytometric analysis, we also evaluated potential synergism between berzosertib and chlorambucil and assessed the influence of berzosertib on cell cycle disturbances induced by the drug. The results demonstrated that berzosertib, even without additional DNA damaging agent, can be effective against canine lymphoma and leukaemia cells at concentrations that were harmless for noncancerous cells, although sensitivity of individual cancer cell lines varied greatly. Cell death occurred through caspase-dependent apoptosis via induction of DNA damage. Berzosertib also acted synergistically with chlorambucil, probably by preventing DNA damage repair as a consequence of S-phase arrest abrogation. In conclusion, ATR inhibition may provide a new therapeutic option for the treatment of canine lymphomas and leukaemias, but further studies are required to determine potential biomarkers of their susceptibility.

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将 ATR 激酶作为犬淋巴瘤和白血病治疗策略的靶点。
共济失调毛细血管扩张症和 Rad3 相关(ATR)激酶是细胞应对 DNA 损伤和复制压力的主要调节因子之一。临床前研究已经证实了以 ATR 为靶点治疗人类癌症的有效性,目前 ATR 抑制剂正在人类肿瘤学领域进行临床开发。在本研究中,我们测试了 ATR 抑制剂 berzosertib 在犬造血癌症体外模型中的抗癌功效。我们使用 MTT 检测法和流式细胞术评估了 berzosertib 在四种已建立的犬淋巴瘤和白血病细胞系中的细胞毒性,并将其与对非癌症犬细胞的活性进行了比较。此外,我们还通过流式细胞仪估算了贝唑舍替处理过的细胞的凋亡水平,并使用 Western 印迹技术评估了作为 DNA 损伤标记的 H2AX 磷酸化。在流式细胞仪分析中,我们还评估了berzosertib和氯霉素之间潜在的协同作用,并评估了berzosertib对氯霉素诱导的细胞周期紊乱的影响。研究结果表明,即使不使用额外的DNA损伤剂,贝唑舍替也能以对非癌细胞无害的浓度有效抑制犬淋巴瘤和白血病细胞,但各癌细胞系的敏感性差异很大。细胞死亡是通过诱导 DNA 损伤,发生依赖于 Caspase 的细胞凋亡。Berzosertib还能与氯霉素产生协同作用,这可能是由于S期停滞的结果阻止了DNA损伤修复。总之,ATR抑制可能会为犬淋巴瘤和白血病的治疗提供一种新的治疗选择,但还需要进一步的研究来确定它们易感性的潜在生物标志物。
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来源期刊
Veterinary and comparative oncology
Veterinary and comparative oncology 农林科学-兽医学
CiteScore
4.80
自引率
9.50%
发文量
75
审稿时长
>24 weeks
期刊介绍: Veterinary and Comparative Oncology (VCO) is an international, peer-reviewed journal integrating clinical and scientific information from a variety of related disciplines and from worldwide sources for all veterinary oncologists and cancer researchers concerned with aetiology, diagnosis and clinical course of cancer in domestic animals and its prevention. With the ultimate aim of diminishing suffering from cancer, the journal supports the transfer of knowledge in all aspects of veterinary oncology, from the application of new laboratory technology to cancer prevention, early detection, diagnosis and therapy. In addition to original articles, the journal publishes solicited editorials, review articles, commentary, correspondence and abstracts from the published literature. Accordingly, studies describing laboratory work performed exclusively in purpose-bred domestic animals (e.g. dogs, cats, horses) will not be considered.
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