title: Apoptotic events induced by maleimides on human acute leukemia cell lines.
abstract: Cyclic imides are known for their antitumor activity, especially the naphthalimide derivatives, such as Mitonafide and Amonafide. Recently, we have demonstrated the cytotoxic effect of a series of naphthalimide derivatives against B16F10 melanoma cells. On the basis of this fact, we have developed a study starting from the synthesis of different cyclic imides and the evaluation of their cytotoxic properties on human acute leukemia cells (K562 and Jurkat). Initially, a screening test was conducted to select the compound with the best cytotoxic effect, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. After this selection, structural modifications were performed in the most active compound to obtain five more derivatives. All compounds presented a good cytotoxic effect. The results of cell cycle analysis, fluorescence microscopy, and Annexin V-FITC assay confirmed that the cells observed in the sub-G0/G1 phase were undergoing apoptosis. From this set of results, cyclic imides 8, 10, and 12 were selected for the evaluation of the mechanisms involved in the apoptotic process. The results demonstrate the involvement of the intrinsic pathway of apoptosis, evidenced by the reduction in mitochondrial potential, an increase in the level of AIF protein expression, a decreased level of expression of anti-apoptotic Bcl-2 protein, and an increased level of expression of pro-apoptotic protein Bax in both K562 and Jurkat cells treated with cyclic imides (8, 10, and 12). Furthermore, cyclic imides 8 and 10 caused an increase in the level of Fas expression in Jurkat cells, indicating the additional involvement of the extrinsic apoptosis pathway. The compounds (8, 10, and 12) also caused a decreased level of expression of anti-apoptotic protein survivin. The biological effects observed with these cyclic imide derivatives in this study suggest promising applications against acute leukemia.
authors.affiliation: Pós-Graduação em Farmácia Universidade Federal de Santa Catarina, UFSC, Campus Trindade, CEP , 88040-900 Florianópolis, Santa Catarina, Brazil.
authors.forename: Karina Elisa
authors.initials: KE
authors.lastname: Machado
authors.forename: Kely Navakoski
authors.initials: KN
authors.lastname: de Oliveira
authors.forename: Haíra Maria Slobodianuk
authors.initials: HM
authors.lastname: Andreossi
authors.forename: Lorena Dos Santos
authors.initials: Ldos S
authors.lastname: Bubniak
authors.forename: Ana Carolina Rabello
authors.initials: AC
authors.lastname: de Moraes
authors.forename: Pâmela Cristina
authors.initials: PC
authors.lastname: Gaspar
authors.forename: Evilásio da Silva
authors.initials: Eda S
authors.lastname: Andrade
authors.forename: Ricardo José
authors.initials: RJ
authors.lastname: Nunes
authors.forename: Maria Cláudia
authors.initials: MC
authors.lastname: Santos-Silva
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D007938:Leukemia / Q000473:pathology*; D008301:Maleimides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D008301:Maleimides