The influence of R substituents in triphenylphosphinegold(I) carbonimidothioates, Ph3PAu[SC(OR)=NPh] (R=Me, Et and iPr), upon in vitro cytotoxicity against the HT-29 colon cancer cell line and upon apoptotic pathways

Abstract

The Ph3PAu[SC(OR)=NPh], R=Me (1), Et (2) and iPr (3), compounds are significantly cytotoxic to the HT-29 cancer cell line with 1 being the most active. Based on human apoptosis PCR-array analysis, caspase activities, DNA fragmentation, cell apoptotic assays, intracellular reactive oxygen species (ROS) measurements and human topoisomerase I inhibition, induction of apoptosis is demonstrated and both the extrinsic and intrinsic pathways of apoptosis have been shown to occur. Compound 1 activates the p73 gene, whereas each of 2 and 3 activates the p53 gene. An additional apoptotic mechanism is exhibited by 2, that is, via the JNK/MAP pathway.

G 2 /M cell cycle arrest on HT-29 cancer cells and toxicity assessment of triphenylphosphanegold(I) carbonimidothioates, Ph 3 PAu[SC(OR) = NPh], R = Me, Et, and iPr, during zebrafish development

“…Specifically, it was demonstrated that 1 activates the p73 gene in contrast to each of 2 and 3 which activate the p53 gene. Further, an additional apoptotic mechanism was induced by 2, namely via the JNK/MAP pathway [22]. Given these promising early results, the present work continues an investigation of 1-3 by delving more deeply into cell apoptosis, release of cytochrome c, cell invasion, cell cycle analysis, gene expression, and in vivo toxicity assessment during zebrafish development.…”

“…The thiocarbamides and triphenylphosphanegold(I) complexes were prepared as described previously [22].…”

“…The cells were treated with the previously determined IC50 concentrations of 1-3, i.e., 11.30, 17.20, and 16.80 µM, respectively [22], and incubated at 37 ºC for 6, 12, and 24 h. After harvesting, the cells were permeabilized, stained, and fixed according to the standard protocols (FlowCellet TM Cytochrome C Kit, Millipore, Germany). The samples were then analyzed using a flow cytometer (FASCalibur ™ , BD Biosciences) equipped with BD cell-fit software TM ; the band pass filter for anti-cytochrome c-FITC is 488 nm.…”

“…were prepared in high yields as described previously [22] and following well established protocols [23], i.e., via the reaction of Ph3PAuCl with the respective ROC(=S)N(H)Ph ligand [24] in the presence of base, and exhibited the same spectroscopic ( 1 H, 13 C{ 1 H} and 31 P{ 1 H}…”

“…It was recently reported that Ph3PAu[SC(OR) = NPh], R = Me (1), Et (2) and iPr (3), exhibited significant cytotoxicity to the HT-29 cancer cell line and induced both intrinsic and extrinsic apoptotic pathways [22]. Specifically, it was demonstrated that 1 activates the p73 gene in contrast to each of 2 and 3 which activate the p53 gene.…”