Antiproliferative and apoptotic effects of two new gold(III) methylsarcosinedithiocarbamate derivatives on human acute myeloid leukemia cells in vitro.
[Au(MSDT)Cl2] (dichloro[methyl N-(dithiocarboxy-kS,kS')-N-methylglicinato]gold(III)) and [Au(MSDT)Br2] (dibromo[methyl N-(dithiocarboxy-kS,kS')-N-methylglicinato]gold(III)) gold(III) dithiocarbamate derivatives are two newly synthesized gold(III) derivatives of methylsarcosinedithiocarbamate, containing a sulfur chelating ligand that is able to bind the metal center strongly, so preventing interactions with sulfur-containing enzymes; in fact these reactions are believed to be responsible for the nephrotoxicity induced by the platinum(II)-based drugs. Their activity has been compared with the well-known platinum-based anticancer agent cisplatin on a panel of acute myelogenous leukemia cell lines representing different French-American-British subtypes and in the Philadelphia-positive cell line K562. Both compounds suppressed, in a dose-dependent manner, colony formation in methylcellulose with ID50 values of about 10-fold lower than that of the reference drug. After a short exposure (18 h), our compounds, but not cisplatin, were able to: downregulate the antiapoptotic molecule Bcl-2, upregulate the proapoptotic molecule Bax and induce apoptosis, as determined by a strong induction of APO2.7 and phosphatidylserine exposure. Finally, after a 72-h exposure, both gold(III) dithiocarbamate derivatives determined modest cell cycle modifications, but induced DNA fragmentation in all myeloid cell lines tested. Altogether, our results indicate that these new gold(III) dithiocarbamate derivatives might represent novel potentially active drugs for the management of myeloid leukemia, able to combine cytostatic and apoptotic activity with reduced nephrotoxicity.
Aldinucci
Donatella
D
Experimental Oncology 2, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy. daldinucci@cro.it
Lorenzon
Debora
D
Stefani
Luigi
L
Giovagnini
Lorena
L
Colombatti
Alfonso
A
Fregona
Dolores
D
D000208:Acute Disease; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000473:pathology; D050607:Organogold Compounds / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis
D000970:Antineoplastic Agents; D050607:Organogold Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C518840:dibromo(methyl N-(dithiocarboxy-kS,kS')-N-methylglicinato)gold(III); C518839:dichloro(methyl N-(dithiocarboxy-kS,kS')-N-methylglicinato)gold(III); D016044:Fusion Proteins, bcr-abl