Aldinucci Donatella, Cattaruzza Lara, Lorenzon Debora, Giovagnini Lorena, Fregona Dolores, Colombatti Alfonso
Experimental Oncology 2, Centro di Riferimento Oncologico, IRCCS, Aviano (PN), Italy.
Oncol Res. 2008;17(3):103-13. doi: 10.3727/096504008785055558.
[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.
[Pd(MSDT)Cl]n钯，氯[甲基N-(二硫代羧基-κS,κS')-N-甲基甘氨酸酯]，以及[Pd(MSDT)Br]n钯，溴[甲基N-(二硫代羧基-κS,κS')-N-甲基甘氨酸酯]，钯（Pd）（II）衍生物是甲基肌氨酸二硫代氨基甲酸盐（MSDT）的两种新合成的Pd（II）衍生物，含有一种能够强烈结合金属中心的硫螯合配体，从而防止与含硫酶相互作用。事实上，这些反应被认为是铂（II）类药物诱导肾毒性的原因。它们的活性已在一组代表不同法国-美国-英国（FAB）亚型的急性髓系白血病（AML）细胞系以及费城（Ph）阳性细胞系K-562中进行评估，并与顺铂进行比较。两种化合物均以剂量依赖性方式抑制甲基纤维素中的集落形成，其半数抑制浓度（ID50）值与参考药物顺铂相当，但ML-3细胞系除外（ID50比顺铂低10倍）。将HL-60、ML-3、NB-4和THP-1细胞系暴露于细胞毒性浓度的[Pd(MSDT)Br]n（5微摩尔）后发现：抗凋亡分子Bcl-2下调，促凋亡分子Bax上调；通过APO2.7和膜联蛋白V染色评估诱导凋亡；线粒体膜通透性增加；以及DNA片段化。在ML-3细胞中，Pd（II）复合物在诱导凋亡方面比顺铂更具活性。最后，[Pd(MSDT)Br]n对造血祖细胞（CFU-GM、CFU-GEMM和BFU-E）的克隆生长显示出抑制作用，其ID50和ID90与顺铂相当。值得注意的是，与正常造血祖细胞（CFU-GEMM、BFU-E和CFU-GM的ID50分别为2.1±0.1、3.8±0.4和2.5±0.2微摩尔）相比，Pd（II）复合物在抑制分化程度较低的AML细胞系KG-1a、HL-60、NB-4、ML-3和THP-1的克隆生长方面更有效（ID50范围为0.02±0.001至0.52±0.04微摩尔）。这些数据表明，与正常定向造血祖细胞相比，髓单核母细胞系的白血病细胞可能是其细胞毒性活性的优先靶点。总之，我们的结果表明，这些新的Pd（II）二硫代氨基甲酸盐衍生物可能代表用于治疗某些选定髓系白血病菌株的新型潜在活性药物，能够将细胞抑制和凋亡活性与降低的毒性相结合。
