Abstract
Cachexia is a common multifactorial syndrome in the advanced stages of cancer and accounts for approximately 20–30% of all cancer-related fatalities. In addition to the progressive loss of skeletal muscle mass, cancer results in impairments in cardiac function. We recently demonstrated that WFA attenuates the cachectic skeletal muscle phenotype induced by ovarian cancer. The purpose of this study was to investigate whether ovarian cancer induces cardiac cachexia, the possible pathway involved, and whether WFA attenuates cardiac cachexia. Xenografting of ovarian cancer induced cardiac cachexia, leading to the loss of normal heart functions. Treatment with WFA rescued the heart weight. Further, ovarian cancer induced systolic dysfunction and diastolic dysfunction Treatment with WFA preserved systolic function in tumor-bearing mice, but diastolic dysfunction was partially improved. In addition, WFA abrogated the ovarian cancer-induced reduction in cardiomyocyte cross-sectional area. Finally, treatment with WFA ameliorated fibrotic deposition in the hearts of tumor-bearing animals. We observed a tumor-induced MHC isoform switching from the adult MHCα to the embryonic MHCβ isoform, which was prevented by WFA treatment. Circulating Ang II level was increased significantly in the tumor-bearing, which was lowered by WFA treatment. Our results clearly demonstrated the induction of cardiac cachexia in response to ovarian tumors in female NSG mice. Further, we observed induction of proinflammatory markers through the AT1R pathway, which was ameliorated by WFA, in addition to amelioration of the cachectic phenotype, suggesting WFA as a potential therapeutic agent for cardiac cachexia in oncological paradigms.
Highlights
Ovarian cancer is one of the leading causes of cancer mortality in the US because this disease is typically diagnosed in advanced stages with widespread metastases
We have reported in our previous study that Withaferin A (WFA) has an anti-inflammatory ability by direct inhibition of NF-κB signaling on skeletal muscle [21], based on this data we hypothesized that WFA could ameliorate the cachectic phenotype exhibited in ovarian cancer
Our xenograft model of ovarian cancer suggests that, given the proper oncological paradigm, female lab animals can and should be utilized in studies of cachexia
Summary
Ovarian cancer is one of the leading causes of cancer mortality in the US because this disease is typically diagnosed in advanced stages with widespread metastases. No screening tests are available for diagnosis at early stages. Very soon after diagnosis, patients experience the clinical symptoms of cachexia: involuntary body weight loss, severe muscle wasting, fatigue, and a decreased response to anticancer therapies; these symptoms lead to a reduction in quality of life and overall survival rate [1,2,3]. The prevalence of cardiac cachexia ranges from 10% to 39%, depending on the disease state [6, 7]. The prognosis for patients with cardiac cachexia is poor, with mortality reaching up to 50% in 18 months [6]. Several cancers have been demonstrated to have a deleterious effect on the heart, but common cancer treatments, such as chemo- and/or radiotherapy, are capable of inducing a cachectic phenotype in and of themselves or exacerbating cardiac dysfunction stemming from the cancer [8, 9]
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