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

Abstract

Herein, ruthenium complexes containing heterocyclic thioamidates [Ru(mmi)(bipy)(dppb)]PF 6 ( 1 ), [Ru(tzdt)(bipy)(dppb)]PF 6 ( 2 ), [Ru(dmp)(bipy)(dppb)]PF 6 ( 3 ) and [Ru(mpca)(bipy)(dppb)]PF 6 ( 4 ) were investigated for their cellular and molecular effects in cancer cell lines. Complexes 1 and 2 were the most potent of the four compounds against a panel of different cancer cell lines in monolayer cultures and showed potent cytotoxicity in a 3D model of multicellular spheroids that formed from human hepatocellular carcinoma HepG2 cells. In addition, both complexes were able to bind to DNA in a calf thymus DNA model. Compared to the controls, a reduction in cell proliferation, phosphatidylserine externalization, internucleosomal DNA fragmentation, and the loss of the mitochondrial transmembrane potential were observed in HepG2 cells that were treated with these complexes. Additionally, coincubation with a pan-caspase inhibitor (Z-VAD(OMe)-FMK) reduced the levels of apoptosis that were induced by these compounds compared to those in the negative controls, indicating that cell death through apoptosis occurred via a caspase-dependent pathway. Moreover, these complexes also induced the phosphorylation of ERK1/2, and coincubation with an MEK inhibitor (U0126), which is known to inhibit the activation of ERK1/2, but not JNK/SAPK and p38 MAPK inhibitors, reduced the complexes-induced apoptosis compared to that in the negative controls, indicating that the induction of apoptotic cell death occurred through ERK1/2 signaling in HepG2 cells. On the other hand, no increase in oxidative stress was observed in HepG2 cells treated with the complexes, and the complexes-induced apoptosis was not reduced with coincubation with the antioxidant N-acetylcysteine or a p53 inhibitor compared to that in the negative controls, indicating that apoptosis occurred via oxidative stress- and p53-independent pathways. Finally, these complexes also reduced the growth of HepG2 cells that were engrafted in C.B-17 SCID mice compared to that in the negative controls. These results indicated that these complexes are novel anticancer drug candidates for liver cancer treatment.

Ruthenium(II) complexes with 6-methyl-2-thiouracil selectively reduce cell proliferation, cause DNA double-strand break and trigger caspase-mediated apoptosis through JNK/p38 pathways in human acute promyelocytic leukemia cells

“…In recent studies, ruthenium(II) complex with methylimidazole induced cell cycle arrest at G 0 /G 1 phase and caused apoptosis through ROS, MAPK and AKT signaling pathways in human lung carcinoma A549 cells 32 , meanwhile ruthenium(II) complex with xanthoxylin caused S-phase arrest and ERK1/2-mediated apoptosis in HepG2 cells by a p53-independent pathway 10 . Similar results were found by Neves and collaborators 16 with ruthenium complexes containing heterocyclic thioamidates that caused caspase-mediated apoptosis through MAPK signaling in HepG2 cells. Ruthenium(II) complexes with piplartine induced MAPK- and p53-dependent apoptosis in HCT116 cells by a ROS-mediated pathway 7,15 .…”

“…Ruthenium-based metallodrugs have been emerged as a novel potential antineoplastic class with less side effect than platinum-based complexes. Therefore, many ruthenium complexes have been synthesized and assessed for their antineoplastic potential in both preclinical and clinical stages, with encouraging outcomes 5–16 .…”

Fasting Increases Iron Export by Modulating Ferroportin 1 Expression Through the Ghrelin/GHSR1α/MAPK Pathway in the Liver

“…ERK is a protein-serine/threonine kinase that can activate nuclear transcription factors and is involved in cell proliferation, differentiation and cell death [39][40][41][42]. It has been confirmed that the proliferative role of ghrelin is related to the activation of its downstream MAPK signaling cascade in multiple types of cells [43,44].…”

Essential Oil from Bark of Aniba parviflora (Meisn.) Mez (Lauraceae) Reduces HepG2 Cell Proliferation and Inhibits Tumor Development in a Xenograft Model

“…Human Hepatocellular Carcinoma Xenograft Model . Human hepatocellular carcinoma xenograft model was carried out as previously reported [30–32] . Fifty C.B‐17 SCID mice (females, 25–30 g) obtained at the animal facilities of the Gonçalo Moniz Institute‐FIOCRUZ (Salvador, Bahia, Brazil) were used.…”