RESUMO
(6-Aminomethylnicotinate)dichloridoplatinum(II) complexes 4 esterified with terpene alcohols were tested on a panel of five human tumor cell lines. While they were accumulated in all cell lines more readily than cisplatin (CDDP), their cytotoxicities were tumor-specific and structure-dependent. Cell lines known to feature elevated levels of antiapoptotic, ion-channel-affecting proteins or otherwise impaired caspase-9 activation responded better to 4 than to CDDP, e.g., the HL-60 leukemia to the fenchyl and bornyl derivatives 4a,b at an IC90 < or = 10 microM. The (-)-menthyl complex 4g was far better accumulated and more efficacious in CDDP-resistant 1411HP male germ cell tumor cells than in the congenerous CDDP-sensitive H12.1 cell line. 4g also broke the CDDP resistance of 518A2 melanoma cells. Cell decay in each case was apoptotic as to TUNEL and Annexin V fluorescence assays. Some complexes 4 seem to positively modulate the permeability of the cell membrane and of blocked mitochondrial anion channels.
Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Monoterpenos/química , Compostos Organoplatínicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , DNA/química , Ensaios de Seleção de Medicamentos Antitumorais , Eletroforese em Gel Bidimensional , Humanos , Marcação In Situ das Extremidades Cortadas , Masculino , Necrose , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Plasmídeos , Espectrofotometria AtômicaRESUMO
Four dipeptide complexes of the type [PtX(2)(dipeptide)] x H(2)O (X=Cl, I, dipeptide=l-methionylglycine, l-methionyl-l-leucine) were prepared. The complexes were characterized by (1)H, (13)C, (195)Pt NMR and infrared spectroscopy, DTG and elemental analysis. From the infrared, (1)H and (13)C NMR spectroscopy it was concluded that dipeptides coordinate bidentately via sulfur and amine nitrogen donor atoms. Confirmed with (13)C and (195)Pt NMR spectroscopy, each of the complexes exists in two diastereoisomeric forms, which are related by inversion of configuration at the sulfur atom. The (1)H NMR spectrum for the platinum(II) complex with l-methionylglycine and chloro ligands exhibited reversible, intramolecular inversion of configuration at the S atom; DeltaG( not equal)=72 kJ mol(-1) at coalescence temperature 349 K was calculated. In vitro cytotoxicity studies using the human tumor cell lines liposarcoma, lung carcinoma A549 and melanoma 518A2 revealed considerable activity of the platinum(II) complex with l-methionylglycine and chloro ligands. Further in vitro cytotoxic evaluation using human testicular germ cell tumor cell lines 1411HP and H12.1 and colon carcinoma cell line DLD-1 showed moderate cytotoxic activity for all platinum(II) complexes only in the cisplatin-sensitive cell line H12.1. Platinum uptake studies using atomic absorption spectroscopy indicated no relationship between uptake and activity. Potential antitumoral activity of this class of platinum(II) complexes is dependent on the kind of ligands as well as on tumor cell type.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Dipeptídeos/farmacologia , Leucina/química , Compostos Organoplatínicos/farmacologia , Platina/química , Animais , Dipeptídeos/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Leucina/farmacologia , Ligantes , Espectroscopia de Ressonância Magnética , Compostos Organoplatínicos/síntese química , Platina/farmacologia , Células Tumorais CultivadasRESUMO
A series of dichloridoplatinum(II) complexes with selective and high cytotoxicity [IC(90)(96h)≤3 µM] against cisplatin-resistant 1411HP testicular cancer cells were identified. They bear stationary 6-aminomethylnicotinate or 2,4-diaminobutyrate ligands esterified with lipophilic terpenyl residues, i.e., (-)/(+)-menthyl, (+)-cedrenyl, (-)-menthoxypropyl, or with a decyl-tethered 1,1,2-triphenylethene. They accumulated to a larger extent in 1411HP cells than in cells of the cisplatin-sensitive H12.1 germ cell tumour. Their mechanism of apoptosis induction differed from that of cisplatin by being independent of p53 and of caspase-3 activation and by an early loss of the mitochondrial membrane potential. The new complexes are promising candidates for the treatment of cisplatin-resistant testicular tumours.
Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Complexos de Coordenação/farmacologia , Resistencia a Medicamentos Antineoplásicos , Platina , Acetilcisteína/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , DNA/química , Fragmentação do DNA , Ensaios de Seleção de Medicamentos Antitumorais , Ativação Enzimática , Etídio/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Substâncias Intercalantes/química , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Neoplasias TesticularesRESUMO
(4-(Tetrahydro-2H-pyran-2-yloxy)R1)R2-diamminedichloroplatinum(II) complexes (1-12) consisting of CDDP linked to THP via aliphatic CH2-spacers were tested in two TGCT cell lines. The most promising compound, 2-(4-(tetrahydro-2H-pyran-2-yloxy)-undecyl)-propane-1,3-diamminedichloroplatinum(II) (12), completely overcame CDDP resistance of 1411HP cells, correlating with increased and accelerated cellular platinum uptake and much faster initiation of apoptotic cell kill. At equitoxic IC90 concentrations, 12 induced accelerated DNA fragmentation and caspase -3 and PARP cleavages. In contrast, DNA platination rate was much lower as compared to CDDP and no upregulation of p53 as well as no initiation of cell cycle arrest were observed. Apoptosis induction by 12 could not be inhibited by pretreatment with caspase-specific inhibitor Z-VAD-Fmk and was accompanied by strong calcium release and generation of reactive oxygen species. To summarize, 12 overcomes CDDP resistance and induces programmed cell death with molecular features different from CDDP, suggesting that both drugs induce apoptosis through different initial pathways.