Atovaquone: An Antiprotozoal Drug Suppresses Primary and Resistant Breast Tumor Growth by Inhibiting HER2/β-Catenin Signaling

Abstract

Breast cancer is the second leading cause of cancer-related mortality in women. In the current study, we evaluated the anticancer effects of an antiprotozoal drug, atovaquone, against several breast cancer cell lines. Our results showed that atovaquone treatment induced apoptosis and inhibited the growth of all the breast cancer cell lines tested, including several patient-derived cells. In addition, atovaquone treatment significantly reduced the expression of HER2, b-catenin, and its downstream molecules such as pGSK-3b, TCF-4, cyclin D1, and c-Myc in vitro. Efficacy of atovaquone was further evaluated in an in vivo tumor model by orthotropic implantation of two highly aggressive 4T1 and CI66 breast cancer cells in the mammary fat pad of female mice. Our results demonstrated that oral administration of atovaquone suppressed the growth of CI66 and 4T1 tumors by 70% and 60%, respectively. Paclitaxel is the first-line chemotherapeutic agent for metastatic breast cancer. We demonstrate that atovaquone administration suppressed the growth of 4T1 paclitaxel-resistant tumors by 40%. Tumors from atovaquone-treated mice exhibited reduced HER2, b-catenin, and c-Myc levels alongside an increase in apoptosis in all the three tumor models when analyzed by Western blotting, IHC, and TUNEL assay. Taken together, our results indicate that atovaquone effectively reduces the growth of primary and paclitaxel-resistant breast tumors. Atovaquone is already in the clinics with high safety and tolerability profile. Therefore, the findings from our studies will potentially prompt further clinical investigation into repurposing atovaquone for the treatment of patients with advanced breast cancer.

Atovaquone Suppresses Triple-Negative Breast Tumor Growth by Reducing Immune-Suppressive Cells

“…This suggests that atovaquone treatment may have a direct effect on tumor cells. This is consistent with our previous studies where we have shown that atovaquone treatment reduced 4T1 and CI66 tumors in mice [ 49 ].…”

“…A few studies, including studies from our lab, have suggested that atovaquone possesses strong anticancer activity [ 45 , 46 , 47 , 48 , 49 ]. A recent study from our lab has shown that atovaquone significantly suppresses the growth of several breast-cancer cells in vitro and in vivo by inhibiting HER2/β-catenin signaling [ 49 ]. To understand the detailed mechanism of action, we evaluated the effects of atovaquone on immune cells associated with breast tumor growth suppression.…”

Atovaquone, chloroquine, primaquine, quinine and tetracycline: antiproliferative effects of relevant antimalarials on Neospora caninum

“…Despite the low CC 50 of atovaquone in Vero cells (3.3 μM), the drug is usually welltolerated (Baggish & Hill, 2002). For example, the CC 50 for HEK293T (human embryonic kidney) is 43 μM (Schuck et al, 2013), indicating a higher susceptibility of Vero cells to the drug, fact also observed in several cell lines of breast cancer (CC 50 : 11-18 μM) (Gupta & Srivastava, 2019). Indeed, there is a report of atovaquone related nephrotoxicity in allogeneic transplanted patients (Mendorf et al, 2015), indicating the susceptibility of some cells of renal origin.…”

Repositioning of Antiparasitic Drugs for Tumor Treatment

“…Mitochondrial respiratory function is not the only target of ATVs. ATVs can degrade HER2 and β-catenin in a proteasome-dependent manner, thereby inhibiting the activation of HER2/β-catenin and triggering apoptosis in cancer cells; however, application of the proteasome inhibitor MG-132 eliminates this effect of ATV ( 180 ). In addition, ATV can also introduce double-stranded breaks in DNA, thereby upregulating phosphorylated ATM and p53 to trigger cycle arrest and apoptosis in cancer cells ( 181 ).…”