A Polyphenol-Rich Muscadine Grape Extract Inhibits HER + Breast Cancer and Protects Against Trastuzumab-Induced Cardiotoxicity

Abstract Objectives Human epidermal growth factor receptor 2 positive (HER2+) breast cancer (BC) is characterized by overexpression of the HER2 receptor. Although targeted HER2 drugs such as trastuzumab (TRZ) are effective for some patients, many patients experience resistance and cardiotoxicity, highlighting the need for additional therapies. The objective of this study was to determine the effects of a polyphenol-rich muscadine grape skin/seed extract (MGE) on TRZ-sensitive and –resistant HER2 + BC and TRZ cardiotoxicity. Methods Human HER2 + BC cells were treated with MGE and/or TRZ and proliferation was analyzed using the IncuCyte® ZOOM. Synergy was assessed using the Chou-Talalay method. Tumor growth and cardiotoxicity were measured in HER2 + xenografts treated with MGE and/or TRZ. TRZ-resistant JIMT-1 cells (2 × 106) were injected in the fourth mammary fat pad of female nude mice and, when tumors reached 50 mm3, mice were divided into four groups: control, MGE, TRZ, MGE + TRZ (n = 10/group, five week treatment). Cardiac parameters were measured using echocardiography and markers of proliferation/oxidative stress were measured by immunohistochemistry. Results The combination of MGE and TRZ inhibited proliferation to a greater extent than either agent alone and was synergistic in TRZ-sensitive SKBR3 cells at five dose combinations. MGE reduced TRZ-resistant JIMT-1 tumor volume by 35% (p ≤ 0.05); however MGE + TRZ inhibited tumor growth to a greater extent (62%) than either agent alone [combination vs. MGE (p ≤ 0.05); combination vs. TRZ (p ≤ 0.01)]. In tumors, MGE + TRZ reduced Ki-67 and activated AKT to a greater extent than MGE or TRZ alone [combination vs. MGE (p ≤ 0.05); combination vs. TRZ (p ≤ 0.0001)]. TRZ significantly reduced left ventricular ejection fraction and fractional shortening, which was prevented by MGE (p ≤ 0.01). Additionally, MGE significantly attenuated the 3-fold TRZ-induced increase in the oxidative stress marker 4-hydroxynonenal in the left ventricle (p ≤ 0.0001). Conclusions MGE inhibited the proliferation of HER2 + BC and was synergistic when combined with TRZ while protecting against TRZ cardiotoxicity. Thus, MGE may serve as an effective therapeutic either administered singly or in combination with TRZ for the treatment of HER2 + BC. Funding Sources Chronic Disease Research Fund.