Antiproliferative and apoptotic effects of two new Pd(II) methylsarcosinedithiocarbamate derivatives on human acute myeloid leukemia cells in vitro

被引:9
作者
Aldinucci, Donatella [1 ]
Cattaruzza, Lara
Lorenzon, Debora
Giovagnini, Lorena [2 ]
Fregona, Dolores [2 ]
Colombatti, Alfonso
机构
[1] IRCCS, Ctr Riferimento Oncol, Clin & Expt Haematol Res Unit, I-33081 Aviano, PN, Italy
[2] Univ Padua, Dept Chem Sci, Padua, Italy
关键词
medicinal inorganic chemistry; palladium compounds; antineoplastic agents; acute myeloid leukemia; therapeutic index;
D O I
10.3727/096504008785055558
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
[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 mu M) 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-la, HL-60, NB-4, ML-3, and THP-1 (ID50 ranging from 0.02 +/- 0.001 to 0.52 +/- 0.04 mu M), compared to normal hematopoietic progenitors (ID50 of 2.1 +/- 0.1, 3.8 +/- 0.4, and 2.5 +/- 0.2 mu M) 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.
引用
收藏
页码:103 / 113
页数:11
相关论文
共 43 条
[1]   Platinum group antitumor chemistry: Design and development of new anticancer drugs complementary to cisplatin [J].
Abu-Surrah, AS ;
Kettunen, M .
CURRENT MEDICINAL CHEMISTRY, 2006, 13 (11) :1337-1357
[2]   CD40L induces proliferation, self-renewal, rescue from apoptosis, and production of cytokines by CD40-expressing AML blasts [J].
Aldinucci, D ;
Poletto, D ;
Nanni, P ;
Degan, M ;
Rupolo, M ;
Pinto, A ;
Gattei, V .
EXPERIMENTAL HEMATOLOGY, 2002, 30 (11) :1283-1292
[3]   Expression of functional interieukin-3 receptors on Hodgkin and Reed-Sternberg cells [J].
Aldinucci, D ;
Poletto, D ;
Gloghini, A ;
Nanni, P ;
Degan, M ;
Perin, T ;
Ceolin, P ;
Rossi, FM ;
Gattei, V ;
Carbone, A ;
Pinto, A .
AMERICAN JOURNAL OF PATHOLOGY, 2002, 160 (02) :585-596
[4]   Antiproliferative and apoptotic effects of two new gold(III) methylsarcosinedithiocarbamate derivatives on human acute myeloid leukemia cells in vitro [J].
Aldinucci, Donatella ;
Lorenzon, Debora ;
Stefani, Luigi ;
Giovagnini, Lorena ;
Colombatti, Alfonso ;
Fregona, Dolores .
ANTI-CANCER DRUGS, 2007, 18 (03) :323-332
[5]   Ruthenium antimetastatic agents [J].
Alessio, E ;
Mestroni, G ;
Bergamo, A ;
Sava, G .
CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2004, 4 (15) :1525-1535
[6]   Satraplatin: an orally available platinum analog for the treatment of cancer [J].
Choy, Hak .
EXPERT REVIEW OF ANTICANCER THERAPY, 2006, 6 (07) :973-982
[7]   A phase I and pharmacodynamic study of fludarabine, carboplatin, and topotecan in patients with relapsed, refractory, or high-risk acute leukemia [J].
Cooper, BW ;
Veal, GJ ;
Radivoyevitch, T ;
Tilby, MJ ;
Meyerson, HJ ;
Lazarus, HM ;
Koc, ON ;
Creger, RJ ;
Pearson, G ;
Nowell, GM ;
Gosky, D ;
Ingalls, ST ;
Hoppel, CL ;
Gerson, SL .
CLINICAL CANCER RESEARCH, 2004, 10 (20) :6830-6839
[8]   Mechanisms of cytotoxicity of selected organogold(III) compounds [J].
Coronnello, M ;
Mini, E ;
Caciagli, B ;
Cinellu, MA ;
Bindoli, A ;
Gabbiani, C ;
Messori, L .
JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (21) :6761-6765
[9]   Apoptosis pathways in cancer and cancer therapy [J].
Debatin, KM .
CANCER IMMUNOLOGY IMMUNOTHERAPY, 2004, 53 (03) :153-159
[10]   Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio predicts outcome in acute myeloid leukemia (AML) [J].
Del Poeta, G ;
Venditti, A ;
Del Principe, MI ;
Maurillo, L ;
Buccisano, F ;
Tamburini, A ;
Cox, MC ;
Franchi, A ;
Bruno, A ;
Mazzone, C ;
Panetta, P ;
Suppo, G ;
Masi, M ;
Amadori, S .
BLOOD, 2003, 101 (06) :2125-2131