Caffeine citrate enhanced cisplatin antitumor effects in osteosarcoma and fibrosarcoma in vitro and in vivo

While multiagent chemotherapy has dramatically improved the prognosis of sarcoma, the novel chemotherapeutics have hardly developed over the past 30 years. Caffeine can induce apoptosis, delays in cell cycle progression and can enhance the cytocidal effects of anti-cancer agents. Citrate has been reported to enhance the cytocidal effect of cisplatin in gastric cancer in vitro. However its effect in sarcoma cells had not been reported. This study was designed to evaluate whether the addition of caffeine, citrate, or caffeine citrate to cisplatin improved its cytocidal effect (cell survival, proliferation, and apoptosis) on human osteosarcoma (HOS), human fibrosarcoma (HT1080) and murine osteosarcoma (LM8) cell lines. We also tested the various combinations in a mouse heterotopic transplantation model in vivo. In cell survival assay, combination index (CI) of caffeine citrate was calculated as a combination of anhydrous caffeine and citric acid, and the synergy was evaluated (CI