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Published on: February 6, 2015
Evaluating the synergistic effects of cisplatin and tamoxifen in canine osteosarcoma cells
Marshall Mays1, Kayden Tanner1, Tomas Lugo1
1School of Veterinary Medicine, Texas Tech University, Amarillo, TX, United States.
Introduction:
Canine osteosarcoma is an aggressive primary bone tumor with a high metastatic rate and poor long-term prognosis. Therapeutic resistance remains a major cause of treatment failure. In human osteosarcoma, sex hormones influence tumor survival and proliferation, and emerging evidence suggests a similar role in canine osteosarcoma. Tamoxifen, a selective estrogen receptor modulator, inhibits estrogen receptor signaling and also exhibits estrogen-independent effects, including suppression of multidrug resistance pathways. Cisplatin is commonly used in canine osteosarcoma treatment; however, resistance limits its effectiveness. Therefore, we hypothesized that tamoxifen could enhance cisplatin efficacy through estrogen-independent mechanisms.
Methods:
Canine osteosarcoma cells were treated with a matrix of tamoxifen and cisplatin concentrations. Cell viability was assessed at 12, 24, and 48 hours using metabolic assays. Cleaved caspase activation and apoptosis-inducing factor expression were evaluated as markers of cell death, while Cyclin D1 and Ki-67 were assessed as markers of cell proliferation. Drug interaction was analyzed using the Zero Interaction Potency model.
Results:
Synergy analysis at 24 hours demonstrated strong synergistic activity between tamoxifen and cisplatin, with a ZIP score of 16.82. Combination treatment reduced metabolic activity and activated apoptotic markers at lower drug concentrations compared with either treatment alone. Although estrogen receptor expression was confirmed, the enhanced cytotoxic effect of tamoxifen appeared to be largely mediated through estrogen-independent mechanisms.
Discussion:
These findings suggest that tamoxifen enhances cisplatin-based combination therapy by promoting cell death in canine osteosarcoma at reduced drug concentrations. Combination therapies targeting estrogen-independent pathways may represent a promising strategy for improving treatment response in metastatic canine osteosarcoma and warrant further investigation.
