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毒素黄素类似物 D43 通过诱导 ROS 介导的细胞凋亡和 DNA 损伤对乳腺癌发挥抗增殖作用。

Toxoflavin analog D43 exerts antiproliferative effects on breast cancer by inducing ROS-mediated apoptosis and DNA damage.

机构信息

School of Life Science, University of Science & Technology of China, Hefei, 230027, Anhui, China.

Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China.

出版信息

Sci Rep. 2024 Feb 18;14(1):4008. doi: 10.1038/s41598-024-53843-1.

DOI:10.1038/s41598-024-53843-1
PMID:38369538
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10874970/
Abstract

Triple-negative breast cancer (TNBC) is regarded as the deadliest subtype of breast cancer because of its high heterogeneity, aggressiveness, and limited treatment options. Toxoflavin has been reported to possess antitumor activity. In this study, a series of toxoflavin analogs were synthesized, among which D43 displayed a significant dose-dependent inhibitory effect on the proliferation of TNBC cells (MDA-MB-231 and HCC1806). Additionally, D43 inhibited DNA synthesis in TNBC cells, leading to cell cycle arrest at the G2/M phase. Furthermore, D43 consistently promoted intracellular ROS generation, induced DNA damage, and resulted in apoptosis in TNBC cells. These effects could be reversed by N-acetylcysteine. Moreover, D43 significantly inhibited the growth of breast cancer patient-derived organoids and xenografts with a favorable biosafety profile. In conclusion, D43 is a potent anticancer agent that elicits significant antiproliferation, oxidative stress, apoptosis, and DNA damage effects in TNBC cells, and D43 holds promise as a potential candidate for the treatment of TNBC.

摘要

三阴性乳腺癌（TNBC）因其高度异质性、侵袭性和有限的治疗选择而被认为是最致命的乳腺癌亚型。吐布啡已被报道具有抗肿瘤活性。在这项研究中，合成了一系列吐布啡类似物，其中 D43 对 TNBC 细胞（MDA-MB-231 和 HCC1806）的增殖具有显著的剂量依赖性抑制作用。此外，D43 抑制 TNBC 细胞的 DNA 合成，导致细胞周期停滞在 G2/M 期。此外，D43 持续促进细胞内 ROS 的产生，诱导 DNA 损伤，并导致 TNBC 细胞凋亡。这些作用可以被 N-乙酰半胱氨酸逆转。此外，D43 显著抑制乳腺癌患者来源的类器官和异种移植物的生长，具有良好的生物安全性。总之，D43 是一种有效的抗癌剂，在 TNBC 细胞中引起显著的增殖抑制、氧化应激、凋亡和 DNA 损伤作用，D43 有望成为治疗 TNBC 的潜在候选药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f73/10874970/2565351188fb/41598_2024_53843_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f73/10874970/57e88ea2f5da/41598_2024_53843_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f73/10874970/25126c81e3e8/41598_2024_53843_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f73/10874970/b9889f7dc571/41598_2024_53843_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f73/10874970/f27b1d769ee2/41598_2024_53843_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f73/10874970/2565351188fb/41598_2024_53843_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f73/10874970/57e88ea2f5da/41598_2024_53843_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f73/10874970/25126c81e3e8/41598_2024_53843_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f73/10874970/b9889f7dc571/41598_2024_53843_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f73/10874970/f27b1d769ee2/41598_2024_53843_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f73/10874970/2565351188fb/41598_2024_53843_Fig5_HTML.jpg

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