Cytotoxic and genotoxic activity of fisetin (3, 3', 4', 7-tetrahydroxyflavone) in an osteosarcoma in vitro model

Osteosarcoma (OS) is an aggressive bone tumour which often becomes chemo-resistant to conventional therapy. Therefore, new agents for OS therapy are demanded. Flavonoids are natural compounds often found as food components and in general these compounds are expected to pose lower cytotoxicity to normal cells, compared to conventional chemotherapy drugs. The flavonoid fisetin is a known cytotoxic agent to various cancer cell lines, but to the best of authors' knowledge, fisetin's effects in osteosarcoma cells have not been reported. In this work, SaOS-2 OS cell line was exposed to fisetin for up to 48h, alone and in combination with etoposide, a common chemotherapy drug. SaOs-2 viability was decreased by 35% upon exposure to 60µM Fisetin for 48h, as determined by MTT assay. Drug combination analysis with isobolograms showed that depending on the combination scheme, fisetin can have synergistic cytotoxic effects with etoposide. After 48-h exposure, fisetin up to 50µM induced increase in the % cells in G2/M phase (up to 3.3 fold) and decrease in % cells in G1/G0 phase (down to 0.37 fold). This is the first report on the cytotoxic effects of fisetin as single agent and in combination with etoposide in an osteosarcoma cell line, highlighting the need for further studies using this flavonoid in osteosarcoma in vitro studies.

Acknowledgements: This work was supported by the Portuguese Foundation for Science and Technology (FCT), through the post-doctoral fellowship of J.M.P. Ferreira de Oliveira (SFRH/BPD/74868/2010) and H. Oliveira (SFRH/BPD/48853/2008).

Keywords: fisetin, osteosarcoma, cell cycle, etoposide, combination studies