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

Tingyue Wu; Wenjing Liu; Hui Chen; Lei Hou; Wenlong Ren; Longlong Zhang; Jinhui Hu; Haijun Chen; Ceshi Chen

doi:10.1038/s41598-024-53843-1

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

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

Authors

Tingyue Wu^#^{1

2}, Wenjing Liu^#³, Hui Chen^#⁴, Lei Hou⁵, Wenlong Ren^{1

2}, Longlong Zhang⁶, Jinhui Hu⁷, Haijun Chen⁸, Ceshi Chen^{9

10

11}

Affiliations

¹ School of Life Science, University of Science & Technology of China, Hefei, 230027, Anhui, China.
² 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.
³ The Third Affiliated Hospital, Kunming Medical University, Kunming, 650118, China.
⁴ Key Laboratory of Molecule Synthesis and Function Discovery (Fujian Province University), College of Chemistry, Fuzhou University, Fuzhou, 350116, Fujian, China.
⁵ Department of Breast Disease, Henan Breast Cancer Center, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China.
⁶ Academy of Biomedical Engineering, Kunming Medical University, Kunming, 650500, China.
⁷ The First Hospital of Hunan University of Chinese Medicine, Changsha, 410007, Hunan, China. hujinhui173@163.com.
⁸ Key Laboratory of Molecule Synthesis and Function Discovery (Fujian Province University), College of Chemistry, Fuzhou University, Fuzhou, 350116, Fujian, China. chenhaij@gmail.com.
⁹ 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. chenc@kmmu.edu.cn.
¹⁰ The Third Affiliated Hospital, Kunming Medical University, Kunming, 650118, China. chenc@kmmu.edu.cn.
¹¹ Academy of Biomedical Engineering, Kunming Medical University, Kunming, 650500, China. chenc@kmmu.edu.cn.

^# Contributed equally.

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.

Keywords: DNA damage; N-acetylcysteine (NAC); Patient-derived breast cancer organoids (PDO); ROS; Toxoflavin.

MeSH terms

Apoptosis
Cell Line, Tumor
Cell Proliferation
DNA Damage
Humans
Pyrimidinones*
Reactive Oxygen Species / metabolism
Triazines*
Triple Negative Breast Neoplasms* / genetics

Substances

Reactive Oxygen Species
toxoflavin
Pyrimidinones
Triazines

Abstract

MeSH terms

Substances

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