The riminophenazine agents clofazimine and B669 inhibit the proliferation of cancer cell lines in vitro by phospholipase A sub(2)-mediated oxidative and nonoxidative mechanisms

Clofazimine, a riminophenazine antimicrobial agent, and its analogue B669 were investigated for their effects on FaDu cells, a human squamous carcinoma cell line. These agents, at concentrations within the therapeutic range (0.25-2 mu g/ml), caused a dose-dependent tumor cell cytotoxicosis which was greatly enhanced in the presence of human neutrophils. The neutrophil-mediated increment in tumoricidal activity, but not the direct antitumor effects of the drugs per se, was inhibited by catalase. The treatment of FaDu cells with clofazimine and B669 was associated with enhanced activity of phospholipase A sub(2), as evidenced by increased release of radiolabeled arachidonate and lysophosphatidylcholine from membrane phospholipids. Inhibitors of arachidonic acid metabolism, protein kinase C inhibitors, as well as water and lipid soluble antioxidants failed to protect the cells against the cytotoxic activity of clofazimine and B669. These observations demonstrate that the tumoricidal properties of clofazimine and B669 are probably due to increases in the lysophospholipid content of cell membranes.