Abstract The purpose of this study was to investigate whether cardiac cachexia occurs in the context of ovarian cancer and whether Withaferin A could ameliorate the cachectic phenotype. We believe that treatment with Withaferin A can ameliorate cancer-induced cachexia and preserve heart function. Ovarian cancer is the fifth leading cause of cancer-related deaths among women in the United States. Cachexia is a common syndrome in advanced cancer patients and accounts for approximately 20% of all cancer-related fatalities. Withaferin A is a steroidal lactone with anti-inflammatory properties that is known to inhibit the growth of ovarian cancer and was recently demonstrated to attenuate the skeletal muscle cachectic phenotype induced by a xenograft model of ovarian cancer. The ovarian cancer cell line A2780 was xenografted into severely immunodeficient female NSG mice via an intraperitoneal (i.p.) injection. Tumor-free control groups received an equivalent volume of sterile saline. Following an engraftment period of 8 days, tumor-free and tumor-bearing mice were treated with vehicle or Withaferin A at one of two doses (2 mg/kg or 4 mg/kg) via i.p. injections every 3 days until the end of the study (4 weeks). Bodyweight and grip strength were assessed on a weekly basis. Heart function was evaluated at the terminal week of the study by echocardiography using Vevo3100 system (FUJIFILM VisualSonics Inc.), followed by histological assessment of the heart for evidence of fibrosis and cardiomyocyte size changes. Cancer induced heart failure in female NSG mice (Systolic dysfunction: FS - 35±3.2; diastolic dysfunction: E/A - 0.45±0.12, IVRT - 22±1.2 msec) and reduced cardiac mass (normalized cardiac mass 9±1.1 (tumor-bearing, vehicle-treated) compared to 13±1.3 (tumor-free, vehicle-treated). Treatment with Withaferin A preserved systolic function in tumor-bearing mice (FS - 58±5.2), but diastolic dysfunction was only modestly improved (E/A - 0.83±0.98, IVRT -17±1.2 msec). Further, Withaferin A ameliorated the reduction in myofibrillar cross-sectional area induced by ovarian cancer. Lastly, treatment with Withaferin A ameliorated fibrotic depositions in the hearts in the tumor-bearing animals. In conclusion, ovarian cancer was shown to induce cardiac cachectic phenotype. Further, it was demonstrated that WFA treatment preserved systolic function, reduced diastolic dysfunction, and attenuated the atrophying and fibrotic effects of the xenografted tumors. Citation Format: Natia Q. Kelm, Alex R. Straughn, Mariusz Z. Ratajczak, Sham S. Kakar. Withaferin A attenuates the induction of cardiac cachexia by ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 439.