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,Guirong Zheng,Jingwei Shao,Hongning Chen,Xiang Yang,Tao Li,Lee Jia,Yajun Liu

doi:10.18632/oncotarget.12232

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.

Highlights

Breast cancer is the second leading cause of cancer mortality worldwide [1]
We developed an novel Asp-Ursolic acid (UA) conjugate, which was composed of classical “old drug” aspirin and low toxicity natural product ursolic acid for targeting breast cancer metastasis
Our research suggested that codrug Asp-UA possessed potential metastasis chemoprevention abilities via influencing epithelial– mesenchymal transition (EMT) and epidermal growth factor receptor (EGFR)-mediated pathways and could be a more promising drug candidate for the prevention and/or treatment of breast cancer metastasis

Summary

Introduction

Breast cancer is the second leading cause of cancer mortality worldwide [1]. Invasion and metastasis, which is estimated to be responsible for approximately 90% of all cancer deaths [2, 3], is the primary factor that results in the failure of breast cancer treatment and poor prognosis. Traditional therapies of breast cancer include some surgery, radiation therapy and chemotherapy, among which chemotherapy still remains the backbone for treatment of metastatic breast cancer. Traditional chemotherapy brings about severe side-effects and often lacks the ability to selectively target the cancer metastasis cascade, leading to distant relapse and repeated recurrence. It is urgently needed to find safe and efficient cancer metastasis preventive agents for cancer survivors in this disease

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Conclusion