A novel ruthenium complex with xanthoxylin induces S-phase arrest and causes ERK1/2-mediated apoptosis in HepG2 cells through a p53-independent pathway

Abstract

Ruthenium-based compounds have gained great interest due to their potent cytotoxicity in cancer cells; however, much of their potential applications remain unexplored. In this paper, we report the synthesis of a novel ruthenium complex with xanthoxylin (RCX) and the investigation of its cellular and molecular action in human hepatocellular carcinoma HepG2 cells. We found that RCX exhibited a potent cytotoxic effect in a panel of cancer cell lines in monolayer cultures and in a 3D model of multicellular cancer spheroids formed from HepG2 cells. This compound is detected at a high concentration in the cell nuclei, induces DNA intercalation and inhibits DNA synthesis, arresting the cell cycle in the S-phase, which is followed by the activation of the caspase-mediated apoptosis pathway in HepG2 cells. Gene expression analysis revealed changes in the expression of genes related to cell cycle control, apoptosis and the MAPK pathway. In addition, RCX induced the phosphorylation of ERK1/2, and pretreatment with U-0126, an MEK inhibitor known to inhibit the activation of ERK1/2, prevented RCX-induced apoptosis. In contrast, pretreatment with a p53 inhibitor (cyclic pifithrin-α) did not prevent RCX-induced apoptosis, indicating the activation of a p53-independent apoptosis pathway. RCX also presented a potent in vivo antitumor effect in C.B-17 SCID mice engrafted with HepG2 cells. Altogether, these results indicate that RCX is a novel anticancer drug candidate.

A novel platinum complex containing a piplartine derivative exhibits enhanced cytotoxicity, causes oxidative stress and triggers apoptotic cell death by ERK/p38 pathway in human acute promyelocytic leukemia HL-60 cells

“…The design of metallodrug-based compounds is an interesting strategy in medicinal chemistry [24] , [25] , [26] , [27] , [28] , [29] , [30] . The most important metallodrug-based compounds are the platinum-based antineoplastic agents.…”

Ru(II)-Thymine Complex Causes Cell Growth Inhibition and Induction of Caspase-Mediated Apoptosis in Human Promyelocytic Leukemia HL-60 Cells

“…Other ruthenium complexes have been previously reported as potent cytotoxic agents, including cyclometalated ruthenium β-carboline complexes, which were cytotoxic to lung, liver, breast, and cervical cancers [ 8 ]; piplartine-containing ruthenium complexes, which were cytotoxic to colon, tongue, liver, breast, skin, and hematological cancers [ 5 ]; a ruthenium complex with xanthoxylin, which was cytotoxic to colon, breast, liver, tongue, gastric, skin, and hematological cancers [ 9 ]; ruthenium imidazole complexes, which were cytotoxic to lung, liver, breast, and cervical cancers [ 19 ]; and, a ruthenium-based 5-fluorouracil complex, which had enhanced cytotoxicity to breast, colon, liver, tongue, skin, and hematological cancers [ 10 ]. The IC 50 values of these compounds are below 10 μM for most of the tested cancer cell lines.…”

“…In addition, these complexes induce cytoprotective autophagy via the ROS-mediated extracellular signal–regulated kinase (ERK) signaling pathway, and the inhibition of autophagy could facilitate cell apoptosis [ 19 ]. The ruthenium complex with xanthoxylin induces S-phase arrest and causes ERK1/2-mediated apoptosis in HepG2 cells through a p53-independent pathway [ 9 ]. The ruthenium complexes with phenylterpyridine derivatives trigger death receptor-mediated apoptosis in A375 cells [ 23 ].…”

“…Therefore, many ruthenium complexes have been designed and synthesized with several ligands, resulting in metallodrugs with action in cancer cells of different histological types. Interestingly, this feature is strictly dependent on the nature of the ligands, and the complexes can act via diverse mechanisms, including induction of reactive oxygen species (ROS), binding of DNA, and cell death via apoptosis pathways [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. In particular, NAMI-A ([ImH][trans-RuCl 4 (DMSO)(Im)], where Im = imidazole and DMSO = dimethylsulfoxide) and KP1019 ([IndH][trans-RuCl 4 (Ind) 2 ], where Ind = indazole) are currently in phase I/II clinical trials, with promising results [ 11 , 12 ].…”

Applications of Ruthenium Complex in Tumor Diagnosis and Therapy

“…Some ruthenium complexes act on telomere DNA, some interfere with replication and transcription of DNA, and others inhibit related enzymes ( Kurzwernhart et al, 2012 ; Jain et al, 2018 ). Furthermore, ruthenium complexes can block the cell cycle ( Kou et al, 2012 ; Wang et al, 2016 ; De Carvalho et al, 2018 ) and induce the formation of DNA photocrosslinking products to prevent RNA polymerization enzymes or exonucleases from binding to DNA, thereby causing tumor cell apoptosis ( Le Gac et al, 2009 ; Rickling et al, 2010 ). Studies have found that some dinuclear and polynuclear Ru(II) polypyridyl complexes bind stably to the G-quadruplex (G4-DNA) structure of telomere DNA ( Hiyama et al, 1995 ; Ambrus et al, 2006 ), inhibiting telomerase activity and blocking the function of DNA replication, thus, preventing normal cells from developing into immortalized tumor cells ( Rajput et al, 2006 ; Shi et al, 2008 ).…”