Exploring the Cytotoxicity, Uptake, Cellular Response, and Proteomics of Mono- and Dinuclear DNA Light-Switch Complexes

Abstract

Drug resistance to platinum chemotherapeutics targeting DNA often involves abrogation of apoptosis, and has emerged as a significant challenge in modern, non-targeted chemotherapy. Consequently, there is great interest in the anti-cancer properties of metal complexes-particularly those that interact with DNA-and mechanisms of consequent cell death. Herein we compare a parent cytotoxic complex [Ru(phen)2(tpphz)] 2+ [phen = 1,10-phenanthroline, tpphz = tetrapyridyl [3,2-a:2',3'-c:3'',2''-h:2''',3'''-j] phenazine], with a mononuclear analogue with modified intercalating ligand, [Ru(phen)2(taptp)] 2+ ,[taptp = 4,5,9,18-tetraazaphenanthreno[9,10-b] triphenylene], and two structurally related di-nuclear, tpphz-bridged, heterometallic complexes, RuRe and RuPt. These changes result in a switch from intercalation to groove binding DNA interaction, concomitant reduction in cytotoxic potency, but no significant change in relative cytotoxicity toward platinum-resistant A2780CIS cancer cells, indicating that DNA interaction mode is not critical for the mechanism of platinum resistance. All variants exhibited a light-switch effect, which for the first time, was exploited to investigate timing of cell death by live cell microscopy. Surprisingly, cell death occurred rapidly as a consequence of oncosis, characterized by loss of cytoplasmic volume control, absence of significant mitochondrial membrane potential loss, and lack of activation of apoptotic cell death markers. Importantly, a novel, quantitative proteomic analysis of the A2780 cell genome following exposure to either mononuclear complex reveals changes in protein expression associated with global cell responses to oxidative stress, and DNA replication/repair cellular pathways. This combination of a multiple targeting modality and induction of a non-apoptotic death mechanism makes these complexes highly promising chemotherapeutic cytotoxicity leads.

Mononuclear ruthenium(ii) theranostic complexes that function as broad-spectrum antimicrobials in therapeutically resistant pathogens through interaction with DNA

“…13,52 Metal complexes like 4 2+ containing ligands with extended aromatic systems meet many of the criteria determined to enhance uptake into Gram-negative bacteria, in that they are polar, amphiphilic, rigid, possess low globularity, and incorporate amine sites. 33,34 In fact, most of these criteria are also met by the previously reported dinuclear analogues of 4 2+ ; yet, the activity of these complexes are greatly lowered against Gram-positive pathogens such as therapeutically resistant S. aureus, whilst complex 4 2+ maintains its activity even in an MRSA strain. This divergence is down to the different uptake mechanisms of [{Ru(TMP) 2 } 2 (tpphz)] 4+ and 4 2+ by Gram-positive bacteria.…”

“…In previous studies, involving related complexes and eukaryotic cells aimed at creating anticancer leads, it was found the Ru II (tpphz) fragment was vital for bioactivity, as changing the ligand to dppz resulted in complete loss of activity toward cancer cells. 33,34 To investigate the importance of the tpphz ligand on the potential antimicrobial activity of complexes 1 2+ -4 2+ , dppz-based analogues, 5 2+ and 6 2+ were also synthesized.…”

Co-inhibition of HDAC and MLL-menin interaction targets MLL-rearranged acute myeloid leukemia cells via disruption of DNA damage checkpoint and DNA repair

“…2b) and MV4-11 cells (Additional file 1: Figure S3B), compared to each single agent. As loss of mitochondrial membrane potential (MMP) plays a crucial role in the initiation of intrinsic mitochondrion-dependent apoptotic cascade [25], we next examined the effect of chidamide and MI-3 individually or in combination on MMP. Consistent with the results for apoptosis, combined treatment with chidamide and MI-3 also induced loss of MMP, reflected by impaired mitochondrial depolarization indicated by markedly decreased fluorescence intensity ratio between JC-1 aggregate and monomer (Fig.…”

Increased Lipophilicity of Halogenated Ruthenium(II) Polypyridyl Complexes Leads to Decreased Phototoxicity in vitro when Used as Photosensitizers for Photodynamic Therapy

“…Indeed, targeting essential cell organelles such as mitochondria, nucleus, lysosomes, Golgi apparatus and endoplasmic reticulum have proven to be effective in increasing the efficacy of anticancer drugs, including PDT PSs. [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] In particular, targeting the nucleus, and more specifically DNA, seems especially attractive, considering the clinical and commercial success of cisplatin. [39] In this context, the complex [Ru(bpy) 2 dppz] 2 + (bpy = bipyridine; dppz = dipyrido[3,2-a:2',3'-c]phenazine; Figure 2) and its derivatives have been studied for their exceptional DNAintercalating properties and light switch effect.…”