TY - JOUR
T1 - Antiproliferative and apoptotic effects of two new Pd(II) methylsarcosinedithiocarbamate derivatives on human acute myeloid leukemia cells in vitro
AU - Aldinucci, Donatella
AU - Cattaruzza, Lara
AU - Lorenzon, Debora
AU - Giovagnini, Lorena
AU - Fregona, Dolores
AU - Colombatti, Alfonso
PY - 2008
Y1 - 2008
N2 - [Pd(MSDT)Cl]n palladium, chloro[methyl N-(dithiocarboxy-kS, kS′)-N-methylglycinate], and [Pd(MSDT) Br]n palladium, bromo[methyl N-(dithiocarboxy-kS,kS′)-N-methylglycinate], palladium (Pd)(II) derivatives are two newly synthesized Pd(II) derivatives of methylsarcosinedithiocarbamate (MSDT), containing a sulfur chelating ligand that is able to strongly bind the metal center, so preventing interactions with sulfur-containing enzymes. In fact, these reactions are believed to be responsible for the nephrotoxicity induced by platinum (II)-based drugs. Their activity has been evaluated in a panel of acute myeloid leukemia (AML) cell lines representing different French-American-British (FAB) subtypes and in the Philadelphia (Ph)-positive cell line K-562 and compared to cisplatin. Both compounds suppressed, in a dose-dependent manner, colony formation in methylcellulose with ID50 values comparable to those of the reference drug cisplatin, excluding the ML-3 cell line (ID50 10-fold lower than cisplatin). Exposure of HL-60, ML-3, NB-4, and THP-1 cell lines to a cytotoxic concentration of [Pd(MSDT)Br]n (5 μM) determined: downregulation of the antiapoptotic molecule Bcl-2, upregulation of the proapoptotic molecule Bax; apoptosis induction, as evaluated by APO2.7 and annexin V staining; mitochondrial membrane permeabilization; and DNA fragmentation. In ML-3 cells the Pd(II) complexes were more active than cisplatin in apoptosis induction. Finally, [Pd(MSDT)Br]n showed an inhibitory effect on clonogenic growth of hematopoietic progenitors (CFU-GM, CFU-GEMM, and BFU-E) with both ID50 and ID90 comparable to those of cisplatin. Remarkably, the Pd(II) complex was more potent in inhibiting the clonogenic growth of the less differentiated AML cell lines KG-1a, HL-60, NB-4, ML-3, and THP-1 (ID50 ranging from 0.02 ± 0.001 to 0.52 ± 0.04 μM), compared to normal hematopoietic progenitors (ID50 of 2.1 ± 0.1, 3.8 ± 0.4, and 2.5 ± 0.2 μM) for CFU-GEMM, BFU-E, and CFU-GM, respectively). These data suggest that leukemic cells of myelomonoblast lineage might represent a preferential target for its cytotoxic activity compared to normal committed hemopoietic progenitor cells. Altogether, our results indicate that these new Pd(II) dithiocarbamate derivatives might represent novel potentially active drugs for the management of some selected myeloid leukemia strains, able to conjugate cytostatic and apoptotic activity with reduced toxicity.
AB - [Pd(MSDT)Cl]n palladium, chloro[methyl N-(dithiocarboxy-kS, kS′)-N-methylglycinate], and [Pd(MSDT) Br]n palladium, bromo[methyl N-(dithiocarboxy-kS,kS′)-N-methylglycinate], palladium (Pd)(II) derivatives are two newly synthesized Pd(II) derivatives of methylsarcosinedithiocarbamate (MSDT), containing a sulfur chelating ligand that is able to strongly bind the metal center, so preventing interactions with sulfur-containing enzymes. In fact, these reactions are believed to be responsible for the nephrotoxicity induced by platinum (II)-based drugs. Their activity has been evaluated in a panel of acute myeloid leukemia (AML) cell lines representing different French-American-British (FAB) subtypes and in the Philadelphia (Ph)-positive cell line K-562 and compared to cisplatin. Both compounds suppressed, in a dose-dependent manner, colony formation in methylcellulose with ID50 values comparable to those of the reference drug cisplatin, excluding the ML-3 cell line (ID50 10-fold lower than cisplatin). Exposure of HL-60, ML-3, NB-4, and THP-1 cell lines to a cytotoxic concentration of [Pd(MSDT)Br]n (5 μM) determined: downregulation of the antiapoptotic molecule Bcl-2, upregulation of the proapoptotic molecule Bax; apoptosis induction, as evaluated by APO2.7 and annexin V staining; mitochondrial membrane permeabilization; and DNA fragmentation. In ML-3 cells the Pd(II) complexes were more active than cisplatin in apoptosis induction. Finally, [Pd(MSDT)Br]n showed an inhibitory effect on clonogenic growth of hematopoietic progenitors (CFU-GM, CFU-GEMM, and BFU-E) with both ID50 and ID90 comparable to those of cisplatin. Remarkably, the Pd(II) complex was more potent in inhibiting the clonogenic growth of the less differentiated AML cell lines KG-1a, HL-60, NB-4, ML-3, and THP-1 (ID50 ranging from 0.02 ± 0.001 to 0.52 ± 0.04 μM), compared to normal hematopoietic progenitors (ID50 of 2.1 ± 0.1, 3.8 ± 0.4, and 2.5 ± 0.2 μM) for CFU-GEMM, BFU-E, and CFU-GM, respectively). These data suggest that leukemic cells of myelomonoblast lineage might represent a preferential target for its cytotoxic activity compared to normal committed hemopoietic progenitor cells. Altogether, our results indicate that these new Pd(II) dithiocarbamate derivatives might represent novel potentially active drugs for the management of some selected myeloid leukemia strains, able to conjugate cytostatic and apoptotic activity with reduced toxicity.
KW - Acute myeloid leukemia
KW - Antineoplastic agents
KW - Medicinal inorganic chemistry
KW - Palladium compounds
KW - Therapeutic index
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M3 - Article
C2 - 18669162
AN - SCOPUS:47549085358
VL - 17
SP - 103
EP - 113
JO - Oncology Research
JF - Oncology Research
SN - 0965-0407
IS - 3
ER -