SB218078 Inhibits Angiogenesis and Epithelial-Mesenchymal Transition in Breast Cancer

Qianxue Wu ¹ Jiawei Xu ² Xin Tang ³ Jin Yu ⁴ Benhua Li ⁵ Yang Jun ⁵ Xiang Zhang ^2*

• ¹ Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, Chongqing Municipality, China
• ² Department of Endocrinology and Breast Surgery, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
• ³ Department of Urology，The First People’s Hospital Of Chongqing Liang Jiang New Area, Chongqing, China
• ⁴ Chongqing Center for Disease Control and Prevention, Chongqing, Chongqing, China
• ⁵ Second People's Hospital of Liangshan Yi Autonomous Prefecture, Xichang, Sichuan, China

Small molecule inhibitors of vascular endothelial growth factor receptor 2 (VEGFR2) are among the most widely used anti-angiogenic agents for tumor treatment, but their adverse effects have become increasingly apparent. In this study, we investigated the small molecule compound SB218078 to assess its effects on tumor angiogenesis and epithelial-mesenchymal transition (EMT) in breast cancer, employing both in vitro and in vivo models. Initially, we evaluated the impact of SB218078 on human umbilical vein endothelial cells (HUVECs) and found that it significantly inhibited their migration, invasion, and tube formation. Next, we utilized Tg(Fli-1:EGFP) zebrafish embryos to examine the angiogenic landscape in vivo. Treatment with SB218078 disrupted the development of intersegmental vessels (ISV), dorsal longitudinal anastomotic vessels, and subintestinal vessels (SIV), leading to impaired tail regeneration in the embryos. We also assessed the effects of SB218078 on breast cancer cells, observing that it effectively reduced proliferation, migration, and invasion across various breast cancer cell lines. Additionally, the administration of SB218078 in xenograft mouse models notably suppressed tumor angiogenesis, which correlated with reduced tumor growth and metastasis. To further investigate the mechanistic pathways involved, we discovered that SB218078 targets Chk1, a downstream factor of the transcription factor ZEB1. Importantly, we established that the downregulation of ZEB1, rather than Snail or Twist, specifically inhibited the development of ISV and SIV in the zebrafish model. In summary, our research identifies SB218078 as a novel anti-angiogenic agent for the treatment of breast cancer, emphasizing its potential as a promising therapeutic option for patients.