Antiproliferative and Apoptotic Effects of Two New Pd(II) Methylsarcosinedithiocarbamate Derivatives on Human Acute Myeloid Leukemia Cells In Vitro

Abstract

[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 microM) 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 microM), compared to normal hematopoietic progenitors (ID50 of 2.1 +/- 0.1, 3.8 +/- 0.4, and 2.5 +/- 0.2 microM) 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.

One‐Pot Synthesis of New (1,3‐Thiazolo[5,4‐b]pyridin‐2‐yl)benzenediols and Their Antiproliferative Activities against Human Cancer Cell Lines

“…It is not characterized by great stability, but it has been used as the reference drug in biological studies of new potential anticancer agents [33]. It was reported that it is stable for 24 h in the admixtures containing NaCl concentrations of 0.3% or larger [34]. Our studies showed that its biological effect starting with the 24-h incubation was stable and did not depend on incubation time.…”

Gold(III) Complexes in the Oncological Preclinical Arena: From Aminoderivatives to Peptidomimetics

“…3) were also tested on a panel of acute myelogenous leukemia cell lines, representing different French-American-British subtypes, and toward the Philadelphia-positive (K562) cells [29]. Compared to the corresponding palladium(II) analogues [30], they were able to inhibit cell growth in all the tested myeloid cell lines with IC 50 values ca. tenfold lower than the reference drug.…”

Organometallic Palladium Complexes with a Water-Soluble Iminophosphorane Ligand As Potential Anticancer Agents

“…The stabilization of Pd(II) compounds by strongly coordinated nitrogen ligands and an appropriate leaving group has been exploited as a synthetic strategy to obtain palladium(II) antitumor complexes . Thus a variety of trans compounds containing bulky monodentate ligands, complexes with bidentate ligands (N–N; P–P, or mixed N–O, N–S), and organometallic derivatives have been prepared. Since the seminal work by Navarro-Ranninger et al on cytotoxic orthometalated palladium complexes (some containing thiosemicarbazone ligands), a few cyclopalladated compounds with potential anticancer activities have been described. − The higher stability of cyclopalladated compounds in physiological media and a lower toxicity to normal cells are promising features for their biological applications .…”