A novel co-drug of aspirin and ursolic acid interrupts adhesion, invasion and migration of cancer cells to vascular endothelium via regulating EMT and EGFR-mediated signaling pathways: multiple targets for cancer metastasis prevention and treatment

// Qiao Tang 1, 2 , Yajun Liu 1, 2 , Tao Li 1, 2 , Xiang Yang 1, 2 , Guirong Zheng 1, 2 , Hongning Chen 1, 2 , Lee Jia 1, 2 , Jingwei Shao 1, 2 1 Cancer Metastasis Alert and Prevention Center, Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou, China 2 Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention, Fuzhou University, Fuzhou, China Correspondence to: Jingwei Shao, email: shaojingwei@fzu.edu.cn , shaojw12@163.com Keywords: cancer metastatic chemoprevention, ursolic acid, aspirin, EMT, EGFR Received: May 27, 2016      Accepted: September 16, 2016      Published: September 24, 2016 ABSTRACT Metastasis currently remains the predominant cause of breast carcinoma treatment failure. The effective targeting of metastasis-related-pathways in cancer holds promise for a new generation of therapeutics. In this study, we developed an novel Asp-UA conjugate, which was composed of classical “old drug” aspirin and low toxicity natural product ursolic acid for targeting breast cancer metastasis. Our results showed that Asp-UA could attenuate the adhesion, migration and invasion of breast cancer MCF-7 and MDA-MB-231 cells in a more safe and effective manner in vitro . Molecular and cellular study demonstrated that Asp-UA significantly down-regulated the expression of cell adhesion and invasion molecules including integrin α6β1, CD44 ,MMP-2, MMP-9, COX-2, EGFR and ERK proteins, and up-regulated the epithelial markers “E-cadherin” and “β-catenin”, and PTEN proteins. Furthermore, Asp-UA (80 mg/kg) reduced lung metastasis in a 4T1 murine breast cancer metastasis model more efficiently, which was associated with a decrease in the expression of CD44. More importantly, we did not detect side effects with Asp-UA in mice such as weight loss and main viscera tissues toxicity. Overall, our research suggested that co-drug Asp-UA possessed potential metastasis chemoprevention abilities via influencing EMT and EGFR-mediated pathways and could be a more promising drug candidate for the prevention and/or treatment of breast cancer metastasis.