The sesquiterpene lactone dehydroleucodine triggers senescence and apoptosis in association with accumulation of DNA damage markers.
Sesquiterpene lactones (SLs) are plant-derived compounds that display anti-cancer effects. Some SLs derivatives have a marked killing effect on cancer cells and have therefore reached clinical trials. Little is known regarding the mechanism of action of SLs. We studied the responses of human cancer cells exposed to various concentrations of dehydroleucodine (DhL), a SL of the guaianolide group isolated and purified from Artemisia douglasiana (Besser), a medicinal herb that is commonly used in Argentina. We demonstrate for the first time that treatment of cancer cells with DhL, promotes the accumulation of DNA damage markers such as phosphorylation of ATM and focal organization of γH2AX and 53BP1. This accumulation triggers cell senescence or apoptosis depending on the concentration of the DhL delivered to cells. Transient DhL treatment also induces marked accumulation of senescent cells. Our findings help elucidate the mechanism whereby DhL triggers cell cycle arrest and cell death and provide a basis for further exploration of the effects of DhL in in vivo cancer treatment models.
Laboratory of Cell Cycle and Cytoskeleton, Instituto de Histología y Embriología Dr. M. H. Burgos (IHEM), Facultad de Ciencias Medicas, Universidad Nacional de Cuyo, Mendoza, Argentina.
Valeria V
VV
Costantino
Sabrina F
SF
Mansilla
Juliana
J
Speroni
Celina
C
Amaya
Darío
D
Cuello-Carrión
Daniel R
DR
Ciocca
Horacio A
HA
Priestap
Manuel A
MA
Barbieri
Vanesa
V
Gottifredi
Luis A
LA
Lopez
D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D056744:Cyclin B1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005819:Genetic Markers; D006367:HeLa Cells; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D008938:Mitosis / Q000187:drug effects; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D005819:Genetic Markers; D007783:Lactones; D012717:Sesquiterpenes; D016159:Tumor Suppressor Protein p53; C079949:dehydroleucodine