title: Induction of apoptosis by a potent caffeic acid derivative, caffeic             acid undecyl ester, is mediated by mitochondrial damage in NALM-6 human B cell             leukemia cells.
abstract: Caffeic acid esters have various biological activities, and we previously reported that undecyl caffeate (caffeic acid undecyl ester, CAUE), a new caffeic acid derivative, has strong pharmacological activity. The present study investigated the cytotoxicity of both CAUE and its parent compound, caffeic acid phenethyl ester (CAPE), and characterized the mechanisms by which they induce apoptosis in the human B cell leukemia cell line NALM-6. Treatment with CAUE reduced cell survival in NALM-6 cells but had no significant effect on the survival of normal lymphocytes. When assessing the 50% inhibitory concentration (IC(50)) for cytotoxicity, CAUE had 10-fold higher activity than CAPE in NALM-6 cells. CAUE treatment resulted in induction of apoptotic features in NALM-6 cells, including cleaved poly (ADP-ribose) polymerase and activated caspase-3. A caspase inhibitor completely blocked CAUE-induced apoptosis. CAUE treatment resulted in a concentration- and time-dependent decrease in both mitochondrial membrane potential and downregulation of Bcl-2 expression. Moreover, CAUE-induced apoptosis was enhanced in the Bcl-2 knockdown condition induced by small interfering RNA. These data suggest that CAUE-induced apoptosis was mediated via an apoptotic intrinsic pathway including mitochondrial damage and was caspase-dependent. These data also suggest that CAUE is a powerful anti-leukemic agent that acts via induction of apoptosis by mitochondrial damage and selective action in leukemia cells.
authors.affiliation: Department of Clinical Pharmacotherapeutics, Tohoku Pharmaceutical                     University, Sendai, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Tomizawa
authors.forename: Syu-ichi
authors.initials: S
authors.lastname: Kanno
authors.forename: Yuu
authors.initials: Y
authors.lastname: Osanai
authors.forename: Akane
authors.initials: A
authors.lastname: Goto
authors.forename: Chizuru
authors.initials: C
authors.lastname: Sato
authors.forename: Shin
authors.initials: S
authors.lastname: Yomogida
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ishikawa
mesh_terms: D000704:Analysis of Variance; D017209:Apoptosis / Q000187:drug effects*; D002109:Caffeic Acids / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D019254:Genes, bcl-2 / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D015448:Leukemia, B-Cell / Q000188:drug therapy* / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D002109:Caffeic Acids; D019253:Proto-Oncogene Proteins c-bcl-2; C581629:caffeic acid undecyl ester; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol