title: Induction of G₂/M arrest, caspase activation and apoptosis by α-santonin derivatives in HL-60 cells.
abstract: Sesquiterpene lactones (SLs) are natural products with a variety of biological activities. Previously, we demonstrated the cytotoxic effects of three new α-santonin derivatives on different tumor cell lines with low toxic effects upon peripheral human leukocytes. Here, we evaluated the mechanism of action triggered by these derivatives. HL-60 cell cycle determined after 24h treatment revealed a significant inhibition on cell-cycle progression and leading to an increasing of cells in G2/M [7.6% and 9.0% for compound 3% and 9.0% and 8.6% for compound 4 (1 and 2 μM, respectively)]. However, after 48 h exposure, all compounds caused G2/M reduction and a significant DNA fragmentation. Compounds 2, 3 and 4 were able to induce apoptosis on leukemia cells, which was corroborated by phosphatidyserine externalization and activation of caspases-3 and -7 after 24h exposure. None of the derivatives analyzed caused depolarization of mitochondrial membrane within 24h of incubation, suggesting the involvement of the extrinsic apoptotic pathway in the death process. The antiproliferative action of these compounds is related to the DNA synthesis inhibition and cell cycle arrest, which probably lead to apoptosis activation. Therefore, these santonin derivatives are promising lead candidates for development of new cytotoxic agents.
authors.affiliation: Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Brazil.
authors.forename: José Roberto Oliveira
authors.initials: JR
authors.lastname: Ferreira
authors.forename: Bruno Coêlho
authors.initials: BC
authors.lastname: Cavalcanti
authors.forename: Patricia Marçal
authors.initials: PM
authors.lastname: da Costa
authors.forename: Francisco Frederico Perlinson
authors.initials: FF
authors.lastname: de Arantes
authors.forename: Elson Santiago
authors.initials: ES
authors.lastname: de Alvarenga
authors.forename: Célia Regina Alvares
authors.initials: CR
authors.lastname: Maltha
authors.forename: Luiz Cláudio
authors.initials: LC
authors.lastname: de Almeida Barbosa
authors.forename: Gardenia Carmen Gadelha
authors.initials: GC
authors.lastname: Militão
authors.forename: Claúdia
authors.initials: C
authors.lastname: Pessoa
authors.forename: Paulo Michel Pinheiro
authors.initials: PM
authors.lastname: Ferreira
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003603:Cytotoxins / Q000494:pharmacology*; D053938:DNA Fragmentation; D016195:G2 Phase; D018922:HL-60 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D012500:Santonin / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D003603:Cytotoxins; D012500:Santonin; D053148:Caspase 3; D053179:Caspase 7