Abstract 7187: Entresto protects against doxorubicin-induced cardiotoxicity in mice model of breast cancer
Authors: Pandit Abhishek , Costas Alanna , Sapkota Biplov , Thota Shilpa , Begum Rizwana , Chintalaramulu Naveen , Green Henry W. , Francis Joseph 
Published: March 2024

Abstract
Doxorubicin (Dox) is a potent chemotherapeutic agent with high efficacy; however, dose-dependent cardiotoxicity undermines its effectiveness in cancer therapies. Entresto, a combination of sacubitril and valsartan (Sac/Val), offers a multi-modal approach. It enhances the beneficial response of the neurohormonal system of the heart while curbing the detrimental effects of the renin-angiotensin-aldosterone system and mitigating further cardiac damage by decreasing sensitivity to natriuretic peptides. The objective of this study is to assess the potential cardioprotective effects of Entresto on doxorubicin-induced cardiotoxicity (DIC) in a mouse model of breast cancer. To achieve this, a syngeneic tumor model of breast cancer was employed. Twenty-five 10-week-old female Balb/c mice were randomly divided into 5 groups: control, Tumor, Tumor + entresto, Tumor + Dox, and Tumor + entresto + Dox. Tumor groups were injected with 4T1 wild-type cells into the mammary fat pad via intraperitoneal injection. Subsequently, after a week, Dox groups were treated with Dox at 8 mg/kg body weight/week for 3 weeks, while control and tumor + entresto received saline. Following Dox treatment, control, and tumor + Dox animals were gavaged daily with saline, while Entresto groups were gavaged with entresto (60 mg/kg) for 3 weeks. Echocardiography assessed cardiac function at baseline and 3 weeks post-DOX treatment. All mice were euthanized at 4 weeks. Our results demonstrated that entresto treatment significantly ameliorated Dox-induced decreases in ejection fraction and fractional shortening while maintaining improved cardiac functions. Entresto also reversed Dox-induced altered levels of cardiac biomarkers (ANP and BNP). Gene and protein expression analyses in heart tissues revealed that entresto modulated the levels of autophagy-related (Beclin-1 and p62), apoptosis-associated (caspase 3 and Bcl-2) and antioxidant-related (Nrf2 and Keap1): genes and proteins expression altered by Dox treatment. Additionally, Entresto attenuated histological evidence of cellular toxicity, apoptosis, and fibrosis in Dox-treated animals with breast cancer. These findings suggest that Entresto confers cardiac protection against DIC in a mouse model of breast cancer without interfering with the antineoplastic effects of Dox. It underscores the potential clinical relevance of Entresto to enhance the safety and efficacy of doxorubicin-based cancer therapies.
Citation Format: Abhishek Pandit, Alanna Costas, Biplov Sapkota, Shilpa Thota, Rizwana Begum, Naveen Chintalaramulu, Henry W. Green, Joseph Francis. Entresto protects against doxorubicin-induced cardiotoxicity in mice model of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7187.