Abstract
Dogs diagnosed with appendicular osteosarcoma typically succumb to metastatic disease within a year of diagnosis. The current standard of care for curative intent, amputation followed by adjuvant chemotherapy, increases survival time but chemoresistance is a major contributor to mortality. Unfortunately, the mechanisms driving the progression of metastatic disease and the development of chemoresistance are unknown. One theory is that autophagy may contribute to chemoresistance by providing neoplastic cells with a mechanism to survive chemotherapy treatment. Our objective was to evaluate the effect of combining an autophagy inhibitor with a standard chemotherapeutic drug on response to chemotherapy in canine appendicular osteosarcoma cells. We hypothesized that combining the autophagy inhibitor spautin-1 with doxorubicin treatment would enhance chemoresponsiveness. Using commercial (D17) and primary cell lines derived from 1° and 2° sites of osteosarcoma, we showed that this combination treatment enhances cell killing and inhibits colony formation. Our findings support the theory that autophagy contributes to chemoresistance in canine appendicular osteosarcoma and indicate that adding an autophagy inhibitor to the standard of care has the potential to improve outcome.
Highlights
Despite being the most common and aggressive bone neoplasm of dogs, the treatment used for canine appendicular osteosarcoma has been largely unchanged for decades [1]
Our investigation evaluated the effect of pre-treatment with the autophagy inhibitor spautin-1 on the response of canine osteosarcoma cells to doxorubicin with respect to cell viability, colony formation, and expression of autophagy related proteins
We hypothesized that doxorubicin would induce autophagy in canine osteosarcoma cells and that the concomitant autophagy inhibition induced by spautin-1 would render these cells more sensitive to chemotherapy
Summary
Despite being the most common and aggressive bone neoplasm of dogs, the treatment used for canine appendicular osteosarcoma has been largely unchanged for decades [1]. The addition of adjuvant chemotherapy post-amputation was investigated in the late 1980s [2,3,4,5,6], was further evaluated and made common practice in the 1990s [3,7,8,9,10], and remains the standard of care for curative intent today. Even with aggressive chemotherapy postamputation, most dogs succumb to metastatic disease less than a year after diagnosis [11]. Multiple attempts have been made to extend survival time by altering the current standard of care for curative intent, as well as to improve the efficacy of treatment against metastatic.
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