Abstract
PurposeOur previous studies have reported the antitumor effect of oleandrin on osteosarcoma; however, its chemosensitizing effect in osteosarcoma treatment is still unknown. Therefore, we explored the sensitizing effects of oleandrin to cisplatin in osteosarcoma and investigated the potential mechanisms.MethodsAfter exposure to oleandrin and/or cisplatin, CCK-8 and colony formation assays, DAPI staining and flow cytometry were performed to detect cell proliferation and apoptosis in 143B, U-2OS and MG-63 osteosarcoma cells. The median-effect analysis was applied to evaluate the combined effect. Western blot was used to determine the expression of related proteins. Osteosarcoma xenografts and histological observations were applied to confirm the combined effect in vivo.ResultsCompared with cisplatin or oleandrin alone, the combined treatment significantly inhibited cell proliferation and induced cell apoptosis. The median-effect analysis indicated a synergistic cytotoxic effect. The combined treatment downregulated Bcl-2 and upregulated Bax and cleaved caspase-3, -8 and -9. And the suppression of caspases reduced cell death. Furthermore, oleandrin alone or with cisplatin, activated the p38 MAPK/Elk-1 pathway. The inhibition of the p38 MAPK pathway increased cell viability and reduced apoptosis. In vivo, the combined treatment was also verified to significantly inhibit tumor growth, induce apoptosis and activate the p38 MAPK pathway.ConclusionsThe combination of oleandrin with cisplatin exerts a synergistic antitumor effect in osteosarcoma, which relates to the activation of the p38 MAPK pathway.
Highlights
Osteosarcoma is the most frequent primary malignant bone tumor and predominantly affects young adults and adolescents [1]
To explore whether OLE enhances the cytotoxicity of DDP, the cells were simultaneously and continuously exposed to increasing concentrations of OLE and DDP at fixed ratios (143B, 1:125; U-2OS, 1:250; and MG-63, 1:500)
The survival rate of osteosarcoma has reached a plateau in recent decades
Summary
Osteosarcoma is the most frequent primary malignant bone tumor and predominantly affects young adults and adolescents [1]. The 5-year overall survival rate has increased from < 20% with surgery alone to 60–65% with the addition of chemotherapy [2]. Recent decades have witnessed no further improvements in survival. Our previous studies reported that OLE has antitumor activity against osteosarcoma in vitro and does not induce the death of normal hFOB1.19 human osteoblast cells [9, 10]. These findings suggest that OLE may be an effective drug therapy for osteosarcoma
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