In vitro study of the pro-apoptotic mechanism of amino acid Schiff base copper complexes on anaplastic thyroid cancer

IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY European Journal of Pharmaceutical Sciences Pub Date : 2025-01-11 DOI:10.1016/j.ejps.2025.107005
Peiran Zhao , Xinyan Zhang , Jianfang Dong , Lianzhi Li , Xiao Meng , Lei Gao
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Abstract

In the endocrine system, anaplastic thyroid cancer (ATC) is extremely aggressive since it inhibits the majority of medications and treatments. Therefore, there is an immediate demand to identify new treatment approaches or drugs to deal with ATC. Recently, amino acid Schiff base copper complexes have received great attention due to their excellent anti-tumor activity. In this research, three copper(II) complexes, [Cu(o-van-D-Trp)(phen)](1), [Cu(o-van-D-Trp)(bipy)](2), [Cu(naph-D-Trp)(bipy)](3), [D-Trp = D-tryptophan; o-van = o-vanillin; naph = 2‑hydroxy-1- naphthaldehyde; phen = 1,10-phenanthroline; bipy = 2,2-biprydine], have been synthesized and investigated as potential anticancer agents. The crystal structure data of the complexes demonstrate that the central copper (II) atom forms a twisted polyhedral environment with nitrogen and oxygen atoms. The MTT results demonstrated that three complexes exhibited superior cytotoxicity against five cell lines of thyroid cancer (Cal-62 cells, ARO cells, KHM-5 m cells, BHP10–3 cells and K1 cells), especially complex 1 with the IC50 values of 0.59±0.05 μM, 2.36±0.47 μM, 1.10±0.87 μM, 0.75±0.09 μM, 1.72±0.06 μM, when cisplatin was used as a control. Research on antitumor mechanisms has demonstrated that complex 1 can significantly reduce the mitochondrial membrane potential, raise autophagy, and produce reactive oxygen species (ROS) in ARO cells in a dose-dependent manner. RNA sequencing study reveals that complex 1 may cause apoptosis in ARO cells and exhibit anticancer efficacy in vitro through ROS-mediated downregulation of Akt and p38 MAPK activation.

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氨基酸席夫碱铜配合物对间变性甲状腺癌促凋亡机制的体外研究。
在内分泌系统中,间变性甲状腺癌(ATC)具有极强的侵袭性,因为它抑制了大多数药物和治疗。因此,迫切需要找到新的治疗方法或药物来治疗ATC。近年来,氨基酸席夫碱铜配合物因其良好的抗肿瘤活性而受到广泛关注。在本研究中,三种铜(II)配合物,[Cu(o-van-D-Trp)(phen)](1), [Cu(o-van-D-Trp)(bipy)](2), [Cu(naph-D-Trp)(bipy)](3), [D-Trp = d -色氨酸;O-van = o-香兰素;Naph = 2‑羟基-1-萘醛;Phen = 1,10-菲罗啉;Bipy = 2,2-biprydine],作为潜在的抗癌药物已被合成和研究。配合物的晶体结构数据表明,中心的铜(II)原子与氮、氧原子形成一个扭曲多面体环境。MTT结果表明,3种复合物对5种甲状腺癌细胞系(Cal-62细胞、ARO细胞、khm - 5m细胞、BHP10-3细胞和K1细胞)均表现出较强的细胞毒性,其中复合物1的IC50值以顺铂为对照分别为0.59±0.05 μM、2.36±0.47 μM、1.10±0.87 μM、0.75±0.09 μM、1.72±0.06 μM。抗肿瘤机制研究表明,复合物1可以显著降低线粒体膜电位,提高自噬,并在ARO细胞中产生活性氧(ROS),并呈剂量依赖性。RNA测序研究表明复合物1可能通过ros介导的下调Akt和p38 MAPK的激活而导致ARO细胞凋亡,并在体外表现出抗癌作用。
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CiteScore
9.60
自引率
2.20%
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248
审稿时长
50 days
期刊介绍: The journal publishes research articles, review articles and scientific commentaries on all aspects of the pharmaceutical sciences with emphasis on conceptual novelty and scientific quality. The Editors welcome articles in this multidisciplinary field, with a focus on topics relevant for drug discovery and development. More specifically, the Journal publishes reports on medicinal chemistry, pharmacology, drug absorption and metabolism, pharmacokinetics and pharmacodynamics, pharmaceutical and biomedical analysis, drug delivery (including gene delivery), drug targeting, pharmaceutical technology, pharmaceutical biotechnology and clinical drug evaluation. The journal will typically not give priority to manuscripts focusing primarily on organic synthesis, natural products, adaptation of analytical approaches, or discussions pertaining to drug policy making. Scientific commentaries and review articles are generally by invitation only or by consent of the Editors. Proceedings of scientific meetings may be published as special issues or supplements to the Journal.
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