Ruthenium Complexes Containing Heterocyclic Thioamidates Trigger Caspase-Mediated Apoptosis Through MAPK Signaling in Human Hepatocellular Carcinoma Cells.

摘要: Herein, ruthenium complexes containing heterocyclic thioamidates [Ru(mmi)(bipy)(dppb)]PF6 (1), [Ru(tzdt)(bipy)(dppb)]PF6 (2), [Ru(dmp)(bipy)(dppb)]PF6 (3) and [Ru(mpca)(bipy)(dppb)]PF6 (4) were investigated for their cellular molecular effects in cancer cell lines. Complexes 1 2 the most potent of four compounds against a panel different lines monolayer cultures showed cytotoxicity 3D model multicellular spheroids that formed from human hepatocellular carcinoma HepG2 cells. In addition, both able to bind DNA calf thymus model. Compared controls, reduction proliferation, phosphatidylserine externalization, internucleosomal fragmentation, loss mitochondrial transmembrane potential observed cells treated with these complexes. Additionally, coincubation pan-caspase inhibitor (Z-VAD(OMe)-FMK) reduced levels apoptosis induced by compared those negative indicating death through occurred via caspase-dependent pathway. Moreover, also phosphorylation ERK1/2, an MEK (U0126), which is known inhibit activation but not JNK/SAPK p38 MAPK inhibitors, complexes-induced induction apoptotic ERK1/2 signaling On other hand, no increase oxidative stress was complexes, antioxidant N-acetylcysteine or p53 stress- p53-independent pathways. Finally, growth engrafted C.B-17 SCID mice controls. These results indicated are novel anticancer drug candidates liver treatment.