A Ruthenium(II) N-Heterocyclic Carbene (NHC) Complex with Naphthalimide Ligand Triggers Apoptosis in Colorectal Cancer Cells via Activating the ROS-p38 MAPK Pathway

Abstract

The p38 MAPK pathway is known to influence the anti-tumor effects of several chemotherapeutics, including that of organometallic drugs. Previous studies have demonstrated the important role of p38 both as a regulator and a sensor of cellular reactive oxygen species (ROS) levels. Investigating the anti-cancer properties of novel 1,8-naphthalimide derivatives containing Rh(I) and Ru(II) N-heterocyclic carbene (NHC) ligands, we observed a profound induction of ROS by the complexes, which is most likely generated from mitochondria (mtROS). Further analyses revealed a rapid and consistent activation of p38 signaling by the naphthalimide-NHC conjugates, with the Ru(II) analogue—termed MC6—showing the strongest effect. In view of this, genetic as well as pharmacological inhibition of p38α, attenuated the anti-proliferative and pro-apoptotic effects of MC6 in HCT116 colon cancer cells, highlighting the involvement of this signaling molecule in the compound’s toxicity. Furthermore, the influence of MC6 on p38 signaling appeared to be dependent on ROS levels as treatment with general- and mitochondria-targeted anti-oxidants abrogated p38 activation in response to MC6 as well as the molecule’s cytotoxic- and apoptogenic response in HCT116 cells. Altogether, our results provide new insight into the molecular mechanisms of naphthalimide-metal NHC analogues via the ROS-induced activation of p38 MAPK, which may have therapeutic interest for the treatment of various cancer types.

Antitumor Activity of Ruthenium(II) Terpyridine Complexes towards Colon Cancer Cells In Vitro and In Vivo

“…The previous research indicates that ruthenium(II) complexes have different effects on the induction of apoptosis in SW480 cells, depending on the ligands in their structure, from a very strong impact where 72% cells were in apoptosis, to moderate, with only 31% apoptotic cells [ 27 ]. In terms of the results related to the ability of ruthenium(II) complexes to induce apoptosis of HCT116 cells, there are results from the previous research that confirm that ruthenium(II) complexes increase the early and late apoptosis of HCT116 in a time- and concentration-dependent manners, but less than oxaliplatin, which is consistent with our results [ 26 , 28 , 29 ].…”

“…Many ruthenium(II) complexes can induce apoptosis by different antiproliferative mechanism, whether inducing G0/G1, S or G2/M phase arrest [ 29 , 33 ]. Ru-1 induced the arrest of CT26 and HCT116 cells in the G2/M phase, and Ru-2 caused G2/M phase arrest in SW480 cells, which is likely related to the molecular changes in the cancer cells ( Figure 7 ).…”

Ruthenium (II) complex cis-[RuII(ŋ2-O2CC7H7O2)(dppm)2]PF6-hmxbato induces ROS-mediated apoptosis in lung tumor cells producing selective cytotoxicity

“…In this sense, the knowledge of molecular and biochemical mechanisms is of great relevance 3 . The probable mechanisms of action of many recently described ruthenium complexes involve apoptosis 27,32,[36][37][38] .…”

Porcine epidemic diarrhea virus infections induce apoptosis in Vero cells via a reactive oxygen species (ROS)/p53, but not p38 MAPK and SAPK/JNK signalling pathways

“…The MAPK pathway is mainly divided into three components including the p38 MAPK, JNK and ERK pathways, and plays an important role in a variety of events in cell processes (Gary and Johnson, 2002;Xu and Zhang, 2015). Increasing evidence has shown that activated p38 MAPK and SAPK/JNK participated in regulation of p53 and ROSmediated apoptosis (Dabiri et al, 2018;Lan et al, 2017;Shang et al, 2017). Therefore, we determined the effect of PEDV infection on the p38 MAPK and SAPK/JNK signal pathways in Vero cells.…”