Abstract
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.
Highlights
OS is the most common malignant primary solid tumor of bone, in children and young adults [1]
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 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
Summary
OS is the most common malignant primary solid tumor of bone, in children and young adults [1]. Standard treatment of OS involves neoadjuvant chemotherapy before definitive surgical resection (mostly limb-sparing or rarely amputation) of the primary tumor, followed by treatment with multiple chemotherapeutic agents or radiotherapy after operation [2, 3]. As one of the effective neoadjuvant chemotherapy drugs for OS treatment, CDDP has been confirmed to have a broad spectrum of cytotoxic and treat possible microscopic metastases, regress or eliminate tumors, and increase the opportunities and possibilities of limbsparing surgery [9]. It remains the pivotal chemotherapeutic agent to overcome inherent tumor resistance for OS therapy, acquired resistance to CDDP and considerable side effects are common and represent a major obstacle to effective treatment of OS. It is urgent to develop less toxic and more effective approaches to overcome these limitations or make up for its flaws [8]
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