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The autophagy inhibitor spautin-1, either alone or combined with doxorubicin, decreases cell survival and colony formation in canine appendicular osteosarcoma cells.

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.

SUBMITTER: Schott CR

PROVIDER: S-EPMC6205606 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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The autophagy inhibitor spautin-1, either alone or combined with doxorubicin, decreases cell survival and colony formation in canine appendicular osteosarcoma cells.

Schott Courtney R CR Ludwig Latasha L Mutsaers Anthony J AJ Foster Robert A RA Wood Geoffrey A GA

PloS one 20181029 10

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 neopl ...[more]

PMID: 30372478

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Project description:BACKGROUND:Cancer is a significant health threat in cats. Chemoresistance is prevalent in solid tumors. The ionophore salinomycin has anti-cancer properties and may work synergistically with chemotherapeutics. The purpose of our study was to determine if salinomycin could decrease cancer cell viability when combined with doxorubicin in feline sarcoma and carcinoma cells. RESULTS:We established two new feline injection-site sarcoma cell lines, B4 and C10, and confirmed their tumorigenic potential in athymic nude mice. B4 was more resistant to doxorubicin than C10. Dose-dependent effects were not observed until 92??M in B4 cells (p =?0.0006) vs. 9.2??M (p =?0.0004) in C10 cells. Dose-dependent effects of salinomycin were observed at 15??M in B4 cells (p =?0.025) and at 10??M in C10 cells (p =?0.020). Doxorubicin plus 5??M salinomycin decreased viability of B4 cells compared to either agent alone, but only at supra-pharmacological doxorubicin concentrations. However, doxorubicin plus 5??M salinomycin decreased viability of C10 cells compared to either agent alone at doxorubicin concentrations that can be achieved in vivo (1.84 and 4.6??M, p <?0.004). In SCCF1 cells, dose-dependent effects of doxorubicin and salinomycin were observed at 9.2 (p =?0.036) and 2.5 (p =?0.0049) ?M, respectively. When doxorubicin was combined with either 1, 2.5, or 5??M of salinomycin in SCCF1 cells, dose-dependent effects of doxorubicin were observed at 9.2 (p =?0.0021), 4.6 (p =?0.0042), and 1.84 (p?=?0.0021) ?M, respectively. Combination index calculations for doxorubicin plus 2.5 and 5??M salinomycin in SCCF1 cells were 0.4 and 0.6, respectively. CONCLUSIONS:We have developed two new feline sarcoma cell lines that can be used to study chemoresistance. We observed that salinomycin may potentiate (C10 cells) or work synergistically (SCCF1 cells) with doxorubicin in certain feline cancer cells. Further research is indicated to understand the mechanism of action of salinomycin in feline cancer cells as well as potential tolerability and toxicity in normal feline tissues.

Dataset Information

The autophagy inhibitor spautin-1, either alone or combined with doxorubicin, decreases cell survival and colony formation in canine appendicular osteosarcoma cells.

Publications

The autophagy inhibitor spautin-1, either alone or combined with doxorubicin, decreases cell survival and colony formation in canine appendicular osteosarcoma cells.

Similar Datasets

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