title: Organopalladium compound 7b targets mitochondrial thiols and induces caspase-dependent apoptosis in human myeloid leukemia cells.
abstract: The advances in the treatment of chronic myeloid leukemia (CML) during the last years were also accompanied by the development of evading strategies by tumor cells, resulting in chemotherapy resistance in some patients. Patented organopalladium compounds derived from the reaction of N,N-dimethyl-1-phenethylamine (dmpa) with [1,2-ethanebis(diphenylphosphine)] (dppe) exhibited a potent antitumor activity in vivo and in vitro in melanoma cells. We showed here that the cyclopalladated derivative [Pd2(R(+))C(2), N-dmpa)2(μ-dppe)Cl2], named compound 7b, was highly effective to promote cell death in the K562 human leukemia cells and its mechanisms of action were investigated. It was shown that compound 7b was able to promote exclusively apoptotic cell death in K562 cells associated to cytochrome c release and caspase 3 activation. This cytotoxic effect was not observed in normal peripheral mononuclear blood cells. The compound 7b-induced intrinsic apoptotic pathway was triggered by the protein thiol oxidation that resulted in the dissipation of the mitochondrial transmembrane potential. The preventive effect of the dithiothreitol on the compound 7b-induced cell death and all downstream events associated to apoptosis confirmed that death signal was elicited by the thiol oxidation. These findings contribute to the elucidation of the palladacycle 7b-induced cell death mechanism and present this compound as a promising drug in the CML antitumor chemotherapy.
authors.affiliation: Centro de Ciências Naturais e Humanas, Universidade Federal do ABC (UFABC), São Paulo, Brazil.
authors.forename: V W R
authors.initials: VW
authors.lastname: Moraes
authors.forename: A C F
authors.initials: AC
authors.lastname: Caires
authors.forename: E J
authors.initials: EJ
authors.lastname: Paredes-Gamero
authors.forename: T
authors.initials: T
authors.lastname: Rodrigues
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004229:Dithiothreitol / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020014:K562 Cells; D007951:Leukemia, Myeloid; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000502:physiology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D009942:Organometallic Compounds / Q000378:metabolism / Q000494:pharmacology*; D010084:Oxidation-Reduction; D013438:Sulfhydryl Compounds / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D024101:Mitochondrial Proteins; D009942:Organometallic Compounds; D013438:Sulfhydryl Compounds; D045304:Cytochromes c; C505407:CASP3 protein, human; D053148:Caspase 3; D004229:Dithiothreitol