The inhibitory effect of lycorine on tumor cell apoptosis induced by polymorphonuclear leukocyte-derived calprotectin.
We recently demonstrated that calprotectin, an abundant calcium-binding protein complex in polymorphonuclear leukocytes (PMNs), has the capacity to induce growth inhibition and apoptotic cell death against a variety of tumor cell lines and normal cells such as fibroblasts. Therefore, calprotectin which is released to extracellular spaces, might cause tissue destruction in severe inflammatory conditions. In search of drugs to suppress the cytotoxic effects of calprotectin, we screened plant products that have been used as Chinese medicines. Using MM46 mouse mammary carcinoma cells as targets, we found that hot water extracts of Crinum asiaticum showed strong inhibition of calprotectin-induced cytotoxicity in vitro. By purification studies, we identified the alkaloid, lycorine, as the active inhibitory molecule. Lycorine inhibits not only induction of MM46 cell death by calprotectin but also inhibits the suppressive effect of calprotectin on target DNA synthesis at a half effective concentration of 0.1-0.5 microg/ml. Lycorine has been reported to posses inhibitory activity against protein translation. Since we previously showed that target protein synthesis is necessary for induction of cell death and that calprotectin actually upregulates the net protein synthesis of MM46 cells, we compared the dose-response relationship between the inhibitory effects of lycorine on calprotectin action and target protein synthesis. Although 1 microg/ml lycorine did not bring about marked inhibition of protein synthesis in MM46 cells without calprotectin, it attenuated the protein synthesis that was augmented by calprotectin to the level of protein synthesis in cells not treated with calprotectin. These results suggest that lycorine inhibition for calprotectin cytotoxicity is not solely due to its inhibitory effect on protein synthesis.
Yui
S
S
Faculty of Pharmaceutical Sciences, Teikyo University, Kanagawa, Japan. sat-yui@pharm.teikyo-u.ac.jp
Mikami
M
M
Kitahara
M
M
Yamazaki
M
M
D047151:Amaryllidaceae Alkaloids; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004347:Drug Interactions; D005260:Female; D039841:Leukocyte L1 Antigen Complex; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D019006:Neural Cell Adhesion Molecules / Q000494:pharmacology*; D009504:Neutrophils / Q000378:metabolism*; D010617:Phenanthridines / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D047151:Amaryllidaceae Alkaloids; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D039841:Leukocyte L1 Antigen Complex; D008562:Membrane Glycoproteins; D019006:Neural Cell Adhesion Molecules; D010617:Phenanthridines; D010936:Plant Extracts; C015330:lycorine