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Research Paper|Volume 15, Issue 16|pp 8258—8274

Acetyl-cinobufagin suppresses triple-negative breast cancer progression by inhibiting the STAT3 pathway

Yufeng Qi1, Haodong Wu2, Tianru Zhu2, Zitian Liu2, Conghui Liu2, Congzhi Yan2, Zhixuan Wu2, Yiying Xu2, Ying Bai3, Lehe Yang2, Dezhi Cheng2, Xiaohua Zhang2, Haiyang Zhao3, Chengguang Zhao2,4, Xuanxuan Dai2
  • 1The First People’s Hospital of Xiaoshan District, Xiaoshan Affiliated Hospital of Wenzhou Medical University, Hangzhou 311200, Zhejiang, China
  • 2The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
  • 3Institute of Life Sciences, Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, Zhejiang, China
  • 4School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
* Equal contribution
Received: October 26, 2022Accepted: July 14, 2023Published: August 28, 2023
https://doi.org/10.18632/aging.204967

Copyright: © 2023 Qi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Background: The incidence of breast cancer (BC) worldwide has increased substantially in recent years. Epithelial-mesenchymal transition (EMT) refers to a crucial event impacting tumor heterogeneity. Although cinobufagin acts as an effective anticancer agent, the clinical use of cinobufagin is limited due to its strong toxicity. Acetyl-cinobufagin, a pre-drug of cinobufagin, was developed and prepared with greater efficacy and lower toxicity.

Methods: A heterograft mouse model using triple negative breast cancer (TNBC) cell lines, was used to evaluate the potency of acetyl-cinobufagin. Signal transducer and stimulator of transcription 3 (STAT3)/EMT involvement was investigated by gene knockout experiments using siRNA and Western blot analysis.

Results: Acetyl-cinobufagin inhibited proliferation, migration, and cell cycle S/G2 transition and promoted apoptosis in TNBC cells in vitro. In general, IL6 triggered the phosphorylation of the transcription factor STAT3 thereby activating the STAT3 pathway and inducing EMT. Mechanistically, acetyl-cinobufagin suppressed the phosphorylation of the transcription factor STAT3 and blocked the interleukin (IL6)-triggered translocation of STAT3 to the cell nucleus. In addition, acetyl-cinobufagin suppressed EMT in TNBC by inhibiting the STAT3 pathway. Experiments in an animal model of breast cancer clearly showed that acetyl-cinobufagin was able to reduce tumor growth.

Conclusions: The findings of this study support the potential clinical use of acetyl-cinobufagin as a STAT3 inhibitor in TNBC adjuvant therapy.