ROLE OF CALCIUM CALMODULIN IN CISPLATIN-INDUCED ACTIVATION OF MURINE BONE-MARROW-DERIVED MACROPHAGES/

In this study we report that the activation of murine bone marrow-deri ved macrophages (BMDM) to the tumoricidal state by cisplatin is a Ca2- and calmodulin-dependent process. Cisplatin induced an increase in [ Ca2+](i) in fura-2/AM-loaded BMDM in a cisplatin concentration-depende nt manner, as evidenced by progressive increase in the relative fluore scence of the treated cells. Cisplatin-treated BMDM also showed a grad ual increase in their ATP level in a cisplatin concentration-dependent manner. There was marked down-regulation of intracellular calcium lev el when the macrophages were pretreated with pertussis toxin or genist ein and subsequently challenged with cisplatin; whereas macrophages tr eated with cholera toxin showed a slight increase in intracellular cal cium, which was significantly upregulated upon cisplatin treatment. Ca lcium-modulating agents EGTA, nifedipine, and TMB-8, and the calmoduli n antagonist W-7, inhibited cisplatin-induced tumoricidal activity of murine BMDM. Supernatants collected from macrophages treated with cisp latin and EGTA, nifedipine, TMB-8, or W-7 demonstrated decreased TNF a nd IL-1 activity in comparison to supernatants collected from macropha ges treated with cisplatin alone.