The synergistic antitumor effect of cinobufagin and cisplatin in human osteosarcoma cell line in vitro and in vivo

Cisplatin (CDDP) has been shown to be a promising anticancer drug that is effective against many types of cancer, which include osteosarcoma (OS). However, its therapeutic application is restricted by its toxicity in normal tissues and by side effects caused in patients. Reduction of the toxicity of CDDP is necessary to improve cancer treatment. In the present study, we attempted to clarify how cinobufagin, a traditional Chinese medicine, enhances CDDP-induced cytotoxicity in OS cells. OS 143B cells were treated with cinobufagin and CDDP alone or in combination. After low dose combined treatments with cinobufagin and CDDP, the effects of these therapeutics on cell proliferation, apoptosis, cell cycle, migration, invasion, and involvement in Notch pathway, as well as tumor growth and metastatic capability were determined. It was found that the combination of low doses of cinobufagin and CDDP markedly inhibited cell activity, motility, and induced apoptosis and cell cycle arrest in S phase, as well as suppressing tumor growth, metastasis and prolonging longer survival of nude mice in OS xenograft models compared with the actions of either drug alone or vehicle. The results also demonstrated that cinobufagin plus CDDP significantly suppressed the Notch pathway. The anticancer mechanism of these two drugs may involve intervention in the Notch signaling, which may contribute to inhibit tumor growth. All of these results suggest that application of lower concentration cinobufagin plus CDDP could produce a synergistic antitumor effect and this finding warrants further investigation for its potential clinical applications in human OS patients.