Antimetastatic potential of Atovaquone against triple negative breast cancer: Involvement of the integrin‐FAK‐Src pathway

Abstract

Triple negative breast cancer (TNBC) is considered to be the most aggressive and malignant neoplasm and is highly metastatic in nature. Metastatic TNBC is difficult to treat and thus leads to poor patient survival. Death of about 90% breast cancer patients is due to metastasis of primary tumor to distant sites. In the current study, we investigated the anti‐metastatic potential of atovaquone, a protozoal drug prescribed for Pneumocystis pneumonia. We show that atovaquone induced apoptosis and reduced the survival of several aggressive metastatic TNBC cell lines including few metastatic patient derived cells. The IC50 of atovaquone was around 11–18 μM in the breast cancer cell lines tested. Additionally, atovaquone treatment significantly reduced the expression of integrinα6, integrin β4, FAK, Src, and Vimentin in MDA‐MB‐231, HCC1806 and 4T1 cells after 72 hours of treatment. In order to study the efficacy of atovaquone in preventing metastasis of breast tumor cells to brain and lungs, we performed three in vivo experiments. We demonstrate that oral administration of 50mg/kg of atovaquone suppressed MDA‐MB‐231 breast tumor growth by 90% in lungs in an intravenous metastatic tumor model. Further anti metastatic effect of atovaquone was determined by intracardiac injection of 4T1‐luc breast tumor cells into the left ventricle of mouse heart. Once breast cancer cells lodged in the brain, mice were treated with 50 mg/kg atovaquone for 15 days. Our results show that atovaquone treatment suppressed the growth of metastatic tumors in brain by 30%. In this model, we also observed 70% and 50% reduced metastasis of breast tumors in lungs and liver, respectively, in atovaquone treated group when compared with control. In intracranial model, the growth of HCC1806‐luc brain tumors in atovaquone treated mice was about 55% less than that of control. Angiogenesis is one of the hallmarks of cancer and plays crucial role in metastasis. Interestingly, we observed reduced levels of VEGF in the cells treated with atovaquone. In‐vivo angiogenesis was evaluated by performing matrigel plug assay in mice. Our results showed reduced angiogenesis in atovaquone treated mice group. Atovaquone treated tumors from these in‐vivo models exhibited reduced metastatic markers and increased apoptosis. Taken together, our results indicate the anti‐metastatic effects of atovaquone in‐vitro and in‐vivo in various breast tumor metastasis models by inhibiting angiogenesis and integrin signaling and provides the rationale for further clinical investigation of atovaquone for breast cancer metastasis.Support or Funding InformationThis work is supported in part by RO1 grant CA129038, awarded by National Cancer Institute, (NIH) to Sanjay K. Srivastava.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.