The Anti‐cancer Effects of Resveratrol on Canine Hemangiosarcoma Cells

Abstract

Hemangiosarcoma (HSA) is a highly malignant tumor of vascular endothelial origin that exhibits aggressive biological behavior. HSAs are more common in dogs than other species including cats, sheep, horses, and cattle. Generally, canine HSAs have poor prognosis. After the complete surgical excision of the primary tumor, the survival time of dogs with HSA is typically short, less than 3 months. Adjuvant treatment with chemotherapy, especially anthracycline‐based regimens such as doxorubicin, can result in modest improvement of survival rates. However, the median survival time of dogs with HSA is still short, even after chemotherapy and surgery. Therefore, there is an urgent need to improve the adjuvant chemotherapeutic regimens in order to reach better clinical outcomes in dogs with HSA. Metformin and resveratrol have been shown to have strong anti‐proliferative and/or pro‐apoptotic properties in several human cancer cell lines. However, the potential anticancer effects of metformin and resveratrol have not been determined in canine HSAs. Therefore, the objective of this study is to investigate the potential growth inhibitory effects of metformin and resveratrol on HSA cell lines when used alone or in combination with doxorubicin. FROG and DD‐1 canine HSA cell lines were treated with varying concentrations of metformin or resveratrol with and without doxorubicin. Cell viability was measured by the MTT assay, and the expression of apoptotic proteins was assessed by western blotting. In contrast to human cell line studies, metformin had a minimal inhibitory effect on the growth of HSA cells. However, resveratrol markedly inhibited the growth of HSA cells, which is in agreement with human cell line studies. In combination, resveratrol and doxorubicin inhibited the growth of both HSA cell lines more than doxorubicin alone. Mechanistically, resveratrol induced apoptosis in HSA cells, and augmented doxorubicin‐induced apoptosis in these cells. Additionally, MTT cell viability of the cardiac‐derived H9c2 cells showed that resveratrol does not augment doxorubicin‐induced cell death in cardiac cells. These findings suggest that resveratrol may have anticancer effects against canine HSA and could be a potential adjunct therapy to the standard‐of‐care anticancer drugs used in canine HSA patients. Since resveratrol has been shown to have both anti‐cancer and cardioprotective effects in rodent models, canine cancer patients can be a perfect translational platform to move the findings of these rodent studies forward to the clinic.Support or Funding InformationResearch reported in this abstract was supported by a Pre‐K Career Development Award from the National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1TR000114. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.