Abstract
Spiciformin (1) is a sesquiterpene lactone with a germacrane skeleton that is found in two Tanacetum species endemic to the Canary Islands. In this study, the cytotoxicities of 1 and its acetyl derivative (2) were evaluated against human tumor cells. These sesquiterpene lactones were cytotoxic against human acute myeloid leukemia (U-937 and HL-60) cells, even in cells over-expressing the pro-survival protein Bcl-2, but melanoma (SK-MEL-1) and human mononuclear cells isolated from blood of healthy donors were more resistant. Both compounds are apoptotic inducers in human leukemia U-937 cells. Cell death was mediated by the processing and activation of initiator and effector caspases and the cleavage of poly(ADP-ribose) polymerase, and it was blocked by a broad-spectrum caspase inhibitor and (in the case of sesquiterpene lactone 2) by the selective caspase-3/7, -8, and -9 inhibitors. In addition, certainly in the case of compound 2, this was found to be associated with a decrease in mitochondrial membrane potential, downregulation of the anti-apoptotic protein Bcl-2, activation of the mitogen-activated protein kinases signaling pathway, and generation of reactive oxygen species. It will, therefore, be relevant to continue characterization of this class of compounds.
Highlights
The discovery of new anticancer agents is of great interest since the currently available drugs against cancer exhibit several critical problems, including serious adverse effects, insufficient effectiveness, and the development of multidrug resistance [1]
The data represent means ± SE of two independent experiments with three determinations each (* p < 0.05, significantly different from untreated control, # p < 0.05, significantly different from sesquiterpene lactone treatment alone). (e) Cells were pretreated with the indicated caspase inhibitors and with 30 μM compound 2, harvested, stained with annexin V-fluoresceine isothiocyanate (FITC) and propidium iodide, and analyzed by flow cytometry. These results demonstrate that both sesquiterpene lactones induce apoptosis by a mechanism dependent on caspase since cell death was completely inhibited by the broad-spectrum caspase inhibitor Z-VAD-FMK
Spiciformin (1) and spiciformin acetate (2) are cytotoxic against the human acute myeloid leukemia cells, including cells that overexpress Bcl-2, and display less cytotoxicity against the melanoma cell line SK-MEL-1 and mononuclear cells isolated from healthy volunteers
Summary
The discovery of new anticancer agents is of great interest since the currently available drugs against cancer exhibit several critical problems, including serious adverse effects, insufficient effectiveness, and the development of multidrug resistance [1]. Sesquiterpene lactones are naturally occurring compounds formed from the condensation of three isoprene units and contain one or more lactone rings. A large number of sesquiterpene lactones exhibit cancer cell cytotoxicity, which depends on the presence of the α-methylene-γ-lactone moiety. This functional group acts as an alkylating agent in a Michael-type reaction with biomolecules cInotn. Sesquiterpene lactones target multiple signal transduc2toifo1n3 pathways involved in survival and cell death. Tanhde parnetsie-inntflsatumdmyaetxopryloraecstitvhietyp, oatnednti(a2l) ciytstocthoxemiciitcyalofstsrpuicctiuforremailnlo(w1)satnhde iatds daicteiotynl odfernievwatisvueb(s2t)itaugeanitnssttohiummparnovteumitsorcycetolltsoxaincdityth. eTihreunpdreesrelynitnsgtumdeychexapnliosmress othfecepllotdeenattihal, icnyctloutdoixnicgittyheodf isspruicpitfioornmoinf m(1it)oacnhdonidtsriaalcemtyelmdberrainveatpivoeten(2t)iaal,gtahiensatcthivuamtiaonn otuf mthoercacsepllasseancdascthadeier aunnddethrleyminigtomgeench-aacntiivsmatesdofpcreoltledineaktihn,aisneclpuadthinwgatyh,ethdeiscrhuapntgioens ionf tmheitoBcchl-o2nfdamriaillympermotberinasneexpporteesnstiioanl,, athnedatchteivgaetnioenraotifotnheofcarsepacatsievecaosxcyagdeenasnpdetchieesm. itogen-activated protein kinase pathway, the changes in the Bcl-2 family proteins expression, and the generation of reactive oxygen species
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