title: Antiproliferative activity of abietane diterpenoids against human tumor cells.
abstract: In the present study, the cytotoxicity of 30 diterpenoids with an abietane or a halimane skeleton was determined against five human tumor cell lines (HL-60, U937, Molt-3, SK-MEL-1, and MCF-7). Diterpenoids containing an abietane skeleton including taxodone (1) and taxodione (2), as well as the semisynthetic derivatives 12, 14, 15, 17, and 22, were the most cytotoxic compounds for human leukemia cells. Overexpression of the protective mitochondrial proteins Bcl-2 and Bcl-x(L) did not confer resistance to abietane diterpene-induced cytotoxicity. Studies performed on HL-60 cells indicated that growth inhibition triggered by compounds 1, 12, 14, and 15 was caused by induction of apoptosis. This was prevented by the nonspecific caspase inhibitor Z-VAD-FMK and, in the case of compounds 14 and 15, reduced by the selective caspase-8 inhibitor Z-IETD-FMK. Cell death induced by these abietane diterpenes was found to be associated with the release of mitochondrial proteins, including cytochrome c, Smac/DIABLO, and AIF (apoptosis-inducing factor), accompanied by dissipation of the mitochondrial membrane potential (ΔΨ), and modulated by inhibition of extracellular signal-regulated kinases signaling and the p38 mitogen-activated protein kinase pathway.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Unidad Asociada al Consejo Superior de Investigaciones Científicas-CSIC, Instituto Canario de Investigación del Cáncer, Universidad de Las Palmas de Gran Canaria, Plaza Dr. Pasteur s/n, 35016 Las Palmas de Gran Canaria, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Burmistrova
authors.forename: M Fátima
authors.initials: MF
authors.lastname: Simões
authors.forename: Patrícia
authors.initials: P
authors.lastname: Rijo
authors.forename: José
authors.initials: J
authors.lastname: Quintana
authors.forename: Jaime
authors.initials: J
authors.lastname: Bermejo
authors.forename: Francisco
authors.initials: F
authors.lastname: Estévez
mesh_terms: D045784:Abietanes / Q000737:chemistry / Q000494:pharmacology*; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D045784:Abietanes; D000590:Amino Acid Chloromethyl Ketones; D000972:Antineoplastic Agents, Phytogenic; D051033:Apoptosis Inducing Factor; D004224:Diterpenes; D009842:Oligopeptides; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C403753:benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C435787:taxodone; D045304:Cytochromes c; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053181:Caspase 8