In vitro and in vivo antitumor studies of potential anticancer agents of platinum ( II ) complexes of dicyclopentadiene and dithiocarbamates

Abstract

Three platinum ( II ) complexes of dicyclopentadiene ( DCP ) and dithiocarbamates ( DTCs ) , namely, [Pt ( η4 -DCP ) ( Me 2 DTC ) ]PF 6 ( 1 ) , [Pt ( η4 - DCP ) ( Et 2 DTC ) ]PF 6 ( 2 ) , and [Pt ( η4 -DCP ) ( Bz 2 DTC ) ]PF 6 ( 3 ) [Me 2 DTC = dimethyldithiocarbamate, Et 2 DTC = diethyldithiocarbamate, and Bz 2 DTC = dibenzyldithiocarbamate] were prepared and characterized by elemental analysis, IR, 1 H, and 13 C Nuclear Magnetic Res- onance spectroscopy. The spectroscopic data indicated the coordination of both DCP and DTC ligands to platinum ( II ) . The solution chemistry of complex 1 revealed that the complexes are stable in both dimethyl sulfoxide ( DMSO ) and 1:1 mixture of DMSO:H 2 O. In vitro cytotoxicity of the complexes relative to cisplatin was tested using MTT [3- ( 4,5-dimethylthiazol-2-yl ) -2,5-diphenyltetrazolium bromide] assay, against CHL-1 ( human melanoma cancer cells ) , MDA-MB-231 ( breast cancer cells ) , A549 ( lung cancer cells ) , and B16 ( murine melanoma cancer cells ) . The antiproliferative effect of all three prepared complexes was found to be significantly higher than cisplatin. Furthermore, flow cytometric analysis of complex 1 showed that the complex induced apoptosis, oxidative stress, mitochon- drial potential depolarization and cell cycle arrest in a concentration-dependent pattern in the CHL-1 cells. Confirmation of apoptosis via gene expression analysis demonstrated down-regulation of anti-apoptotic genes and up-regulation of pro-apoptotic genes in the CHL-1 cells. Wound-healing assays also lent support to the strong cytotoxicity of the complexes. In vivo studies showed a significant reduction of tumor volume at the end of the experiment. In addition, the drug did not change the weight of the mice. In conclusion, complex 1 inhibited cell proliferation in vitro and reduced tumor growth in vivo .