THE INHIBITORY EFFECT OF LYCORINE ON TUMOR-CELL APOPTOSIS INDUCED BY POLYMORPHONUCLEAR LEUKOCYTE-DERIVED CALPROTECTIN

We recently demonstrated that calprotectin, an abundant calcium-bindin g protein complex in polymorphonuclear leukocytes (PMNs), has the capa city to induce growth inhibition and apoptotic cell death against a va riety of tumor cell lines and normal cells such as fibroblasts. Theref ore, calprotectin which is released to extracellular spaces, might cau se tissue destruction in severe inflammatory conditions. In search of drugs to suppress the cytotoxic effects of calprotectin, we screened p lant products that have been used as Chinese medicines. Using MM46 mou se mammary carcinoma cells as targets, we found that hot water extract s of Crinum asiaticum showed strong inhibition of calprotectin-induced cytotoxicity in vitro. By purification studies, we identified the alk aloid, lycorine, as the active inhibitory molecule. Lycorine inhibits not only induction of MM46 cell death by calprotectin but also inhibit s the suppressive effect of calprotectin on target DNA synthesis at a half effective concentration of 0.1-0.5 mu g/ml. Lycorine has been rep orted to posses inhibitory activity against protein translation. Since we previously showed that target protein synthesis is necessary for i nduction of cell death and that calprotectin actually upregulates the net protein synthesis of MM46 cells, we compared the dose-response rel ationship between the inhibitory effects of lycorine on calprotectin a ction and target protein synthesis. Although 1 mu g/ml lycorine did no t bring about marked inhibition of protein synthesis in MM46 cells wit hout calprotectin, it attenuated the protein synthesis that was augmen ted by calprotectin to the level of protein synthesis in cells not tre ated with calprotectin. These results suggest that lycorine inhibition for calprotectin cytotoxicity is not solely due to its inhibitory eff ect on protein synthesis. (C) 1998 Elsevier Science B.V. All rights re served.