title: Involvement of extrinsic and intrinsic apoptotic pathways together with endoplasmic reticulum stress in cell death induced by naphthylchalcones in a leukemic cell line: advantages of multi-target action.
abstract: Chalcones, naturally occurring open-chain flavonoids abundant in plants, have demonstrated anticancer activity in multiple tumor cells. In a previous work, the potential anticancer activity of three naphthylchalcones named R7, R13 and R15 was shown. In this study, the mechanism of actions of these chalcones was originally shown. The chalcones presented concentration and time-dependent cytotoxicity. To determine the type of cell death induced by chalcones, we assessed a series of assays including measurements of the caspase-8, -9 and -12 activities, expression of important apoptosis-related genes and proteins, changes in the cell calcium concentration and cytochrome c release. The activities of caspase-8, -9 and -12 increased after the treatment of L1210 cells with the three compounds. Chalcones R7 and R13 induced an increase of pro-apoptotic proteins Bax, Bid and Bak (only chalcone R13), as well as a decrease in anti-apoptotic Bcl-2 expression. These chalcones also induced an increase in Fas and a decrease in p21 and p53 expression. Chalcone R15 seems to act by a different mechanism to promote cell death, as it did not change the mitochondrion-related proteins, nor did it induce the cytochrome c release. All compounds induced an increase in cell calcium concentration and an increase in CHOP expression, which together with an increase in caspase-12 activity, suggest that chalcones could induce an endoplasmic reticulum (ER) stress. Taken together, these results suggest that chalcones induce apoptosis by different pathways, being an interesting strategy to suggest for cancer therapy.
authors.affiliation: Departamento de Ciências Farmacêuticas, Universidade Federal de Santa Catarina, 88040-900 Florianópolis, SC, Brazil.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Winter
authors.affiliation: Departamento de Química, Universidade Federal de Santa Catarina, 88040-900 Florianópolis, SC, Brazil.
authors.forename: Louise Domeneghini
authors.initials: LD
authors.lastname: Chiaradia
authors.affiliation: Departamento de Ciências Farmacêuticas, Universidade Federal de Santa Catarina, 88040-900 Florianópolis, SC, Brazil.
authors.forename: Adny Henrique
authors.initials: AH
authors.lastname: Silva
authors.affiliation: Departamento de Química, Universidade Federal de Santa Catarina, 88040-900 Florianópolis, SC, Brazil.
authors.forename: Ricardo José
authors.initials: RJ
authors.lastname: Nunes
authors.affiliation: Departamento de Química, Universidade Federal de Santa Catarina, 88040-900 Florianópolis, SC, Brazil.
authors.forename: Rosendo Augusto
authors.initials: RA
authors.lastname: Yunes
authors.affiliation: Departamento de Ciências Farmacêuticas, Universidade Federal de Santa Catarina, 88040-900 Florianópolis, SC, Brazil. Electronic address: tania.pasa@ufsc.br.
authors.forename: Tânia Beatriz
authors.initials: TB
authors.lastname: Creczynski-Pasa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D047188:Chalcones / Q000494:pharmacology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D045304:Cytochromes c / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D015870:Gene Expression; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014709:Vero Cells; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D047188:Chalcones; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; D045304:Cytochromes c; D002118:Calcium
keywords: Chalcones; Endoplasmic reticulum; Extrinsic apoptosis; Intrinsic apoptosis; Leukemia