Abstract
BackgroundOsteosarcoma (OS) is the most common primary bone malignancy with a high propensity for local invasion and distant metastasis. Limited by the severe toxicity of conventional agents, the therapeutic bottleneck of osteosarcoma still remains unconquered. Flavokawain B (FKB), a kava extract, has been reported to have significant anti-tumor effects on several carcinoma cell lines both in vitro and in vivo. Its efficacy and low toxicity profile make FKB a promising agent for use as a novel chemotherapeutic agent.ResultsIn the current study, we investigated the anti-proliferative and apoptotic effects of FKB against human osteosarcomas. Exposure of OS cells to FKB resulted in apoptosis, evidenced by loss of cell viability, morphological changes and the externalization of phosphatidylserine. Apoptosis induced by FKB resulted in activation of Caspase-3/7, -8 and −9 in OS cell lines, 143B and Saos-2. FKB also down-regulated inhibitory apoptotic markers, including Bcl-2 and Survivin and led to concomitant increases in apoptotic proteins, Bax, Puma and Fas. Therefore, the induction of apoptosis by FKB involved both extrinsic and intrinsic pathways. FKB also caused G2/M phase cell cycle arrest, which was observed through reductions in the levels of cyclin B1, cdc2 and cdc25c and increases in Myt1 levels. Furthermore, migration and invasion ability was decreased by FKB in a dose-dependent manner. The cytotoxicity profile showed FKB had significant lower side effects on bone marrow cells and small intestinal epithelial cells compared with Adriamycin.ConclusionsTaken together, our evidence of apoptosis and cell cycle arrest by FKB treatment with less toxicity than the standard treatments provides an innovative argument for the use of FKB as a chemotherapeutic and chemopreventive compound. In vivo experiments utilizing FKB to reduce tumorigenesis and metastatic potential will be crucial to further justify clinical application.
Highlights
Osteosarcoma (OS) is the most common primary bone malignancy with a high propensity for local invasion and distant metastasis
Osteosarcoma is the most common primary malignant tumor arising from bone in children and young adults with a very high propensity for local invasion and distant metastasis
Given that the current chemotherapy regimens have had limited success in improving metastasis-free survival and the poor response of previously treated patients with relapsed osteosarcoma, we investigated the potential application of natural anticancer agents in treatment of osteosarcoma
Summary
Osteosarcoma (OS) is the most common primary bone malignancy with a high propensity for local invasion and distant metastasis. Others, recently demonstrated that flavokawavin B (FKB) induced apoptosis and exhibited both in vitro and in vivo anticancer activity against bladder, prostate, colon, oral, lung cancer cells, and mesenchymal tumors including synovial sarcoma and uterine leiomyosarcoma [5,9,10,11,12,13,14]. These findings encouraged us to investigate the anticancer effects of FKB on OS as a novel compound agent
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