Journal
ANTI-CANCER DRUGS
Volume 18, Issue 3, Pages 323-332Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CAD.0b013e328011ae98
Keywords
acute myeloid leukemia; antineoplastic agents; gold compounds; medicinal inorganic chemistry; nephrotoxicity; therapeutic use
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[Au(MSDT)Cl-2] (dichloro[methyl N-(dithiocarboxy-kS,kS)-N-methylglicinato]gold(III) and [Au(MSDT)Br-2] (dibromo[methyl N-(dithiocarboxy-kS,kS)-N-methylglicinato]gold(ill)) 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.
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