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The aim of anti-cancer therapy is the induction of apoptosis in tumor cells.A body of evidence suggests that second messengers, such as modulations in the intraeellular calcium concentration ([Ca2+]i) could be involved in inducing apoptosis and cell death.Here we tested whether two metal based anti-cancer drugs arsenic trioxide (As2O3) and cisplatin (CDDP) change [Ca2+]i and induce apoptosis and cell death.Confocal imaging with a Ca2+-sensitive dye (fluo-4) was performed for investigating [Ca2+]i dynamics in human neuroblastoma cells.The induction of cell death was assayed using Trypan blue exclusion and Hoechst 33347 staining.Application of either As2O3 (l microM) or CDDP (1 microM) increased [Ca2+]i.Both, transient and sustained [Ca2+]i-increases were observed in response to a single application ofAs2O3 or CDDP.Interestingly arsenic trioxide (As2O3) and cisplatin (CDDP) modulate [Ca2+]i by different mechanisms: As2O3 depletes intracellular calcium stores while CDDP triggers an influx of Ca2+.To investigate whether these mechanisms are independent we co-applied As2O3 and CDDP.The sustained increase of [Ca2+]i showed a clear additive effect.The magnitude of the [Ca2+]i-increase depended on the order of application;the most pronounced effect occurred when the cells were preincubated with CDDP followed by a co-application with As2O3.The higher [Ca2+]i resulted consequently in increased cytotoxicity and apoptosis.Therefore, co-treatment with CDDP and As2O3 may be a more effective anti-cancer therapy then either agent alone.