Atovaquone Suppresses the Growth of Metastatic Triple-Negative Breast Tumors in Lungs and Brain by Inhibiting Integrin/FAK Signaling Axis.

Nehal Gupta,Sanjay K Srivastava

doi:10.3390/ph14060521

Abstract

Triple-negative breast cancer (TNBC) is considered to be the most aggressive and malignant neoplasm and is highly metastatic in nature. In the current study, we investigated the anti-metastatic potential of atovaquone, a protozoal drug prescribed for Pneumocystis pneumonia. We showed that atovaquone induced apoptosis and reduced the survival of several aggressive metastatic TNBC cell lines including metastatic patient-derived cells by reducing the expression of integrin α6, integrin β4, FAK, Src, and Vimentin. In order to study the efficacy of atovaquone in suppressing metastasized breast tumor cells in brain and lungs, we performed three in vivo experiments. We demonstrated that oral administration of 50 mg/kg of atovaquone suppressed MDA-MB-231 breast tumor growth by 90% in lungs in an intravenous metastatic tumor model. Anti-metastatic effect of atovaquone was further determined by intracardiac injection of 4T1-luc breast tumor cells into the left ventricle of mouse heart. Our results showed that atovaquone treatment suppressed the growth of metastatic tumors in lungs, liver and brain by 70%, 50% and 30% respectively. In an intracranial model, the growth of HCC1806-luc brain tumors in atovaquone treated mice was about 55% less than that of control. Taken together, our results indicate the anti-metastatic effects of atovaquone in vitro and in vivo in various breast tumor metastasis models.

Highlights

Breast cancer represents one of the most commonly occurring cancer in women worldwide and is the second leading cause of cancer-related mortality [1]
The lethality of Triple-negative breast cancer (TNBC) is driven by its metastatic potential, which accounts for greater mortality rates, compared to those observed from the primary tumor
Unlike other breast cancer subtypes, there is no effective targeted therapy for TNBC, rendering it very difficult to treat by conventional therapeutic options [51]

Summary

Introduction

Breast cancer represents one of the most commonly occurring cancer in women worldwide and is the second leading cause of cancer-related mortality [1]. TNBC accounts for 15–20% of all breast cancer patients [6]. Prior studies have validated that TNBC is more likely to metastasize to visceral organs and central nervous system than other breast cancer subtypes. It is correlated with poor prognosis and low survival rates [7,8]. Several advancements in diagnosis and therapeutic interventions resulted in improved survival rates, lack of effective therapeutic options for advanced and metastatic TNBC presents it as one of the greatest challenges in oncology drug development [9]. The lethality of TNBC is driven by its metastatic potential, which accounts for greater mortality rates, compared to those observed from the primary tumor

Methods

Results

Conclusion