A three-in-one-bullet for oesophageal cancer: replication fork collapse, spindle attachment failure and enhanced radiosensitivity generated by a ruthenium(<scp>ii</scp>) metallo-intercalator

Gill, Martin R.; Jarman, Paul J.; Halder, Swagata; Walker, Michael G.; Saeed, Hiwa K.; Thomas, Jim A.; Smythe, Carl; Ramadan, Kristijan; Vallis, Katherine A.

doi:10.1039/c7sc03712k

Cited by 35 publications

(46 citation statements)

References 65 publications

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“…In the first proteomic study involving kinetically inert ruthenium complexes, we found that these mononuclear complexes induce protein expression changes that are indicative of both DNA damage and oxidative stress responses. This first observation is consistent with previous studies confirming that binding directly stalls DNA replication forks, 51 however the up-regulation of proteins associated with oxidative stress suggest the complexes have a second mode of action. Although the complexes described by MacDonnell and coworkers are also cytotoxic through oxidative stress they contain ligands that Ð unlike tpphz 131 Ð are themselves redox active in biological conditions.…”

Section: Discussionsupporting

confidence: 92%

“…Complexes investigated in this study Like the dinuclear system, the mononuclear intercalating complex [Ru(phen)2(tpphz)] 2+ , , is taken up by cells, and shows cellular DNA binding; 50 however, it also displays cytotoxicity comparable to cisplatin and its potency is retained even in cisplatinresistant cell lines. 50 Unsurprisingly given its mode of interaction with DNA, , interferes with DNA replication 51 and it is a potent radiosensitizer. 51 Yet, a more detailed understanding of the cellular responses it induces, including cell death mechanisms, is still to be developed.…”

Section: Introductionmentioning

confidence: 99%

“…98 Taken together these data are consistent with the known DNA binding properties of in vitro 50 (Figure 3) as well as its effect on DNA replication in vivo. 51 Importantly, they provide additional detailed insight into the nature of the cellular DNA damage response to and suggest that, in addition to replication fork stalling, binding of to DNA in vivo provokes a requirement for both nucleotide excision and DNA mismatch repair pathways.…”

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confidence: 99%

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

et al. 2018

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2018

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“…Phototoxicity of Ru complexes arises from two different mechanisms. One mechanism is singlet oxygen ( 1 O 2 ) sensitization using Ru complexes for photodynamic therapy (PDT) . The other mechanism is uncaging cytotoxic ligands or Ru species via ligand photosubstitution reactions for photoactivated chemotherapy (PACT) …”

Section: Introductionmentioning

confidence: 99%

Red‐Light‐Controlled Release of Drug–Ru Complex Conjugates from Metallopolymer Micelles for Phototherapy in Hypoxic Tumor Environments

Sun

Yan

Thiramanas

et al. 2018

Adv Funct Materials

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Traditional photodynamic phototherapy is not efficient for anticancer treatment because solid tumors have a hypoxic microenvironment. The development of photoactivated chemotherapy based on photoresponsive polymers that can be activated by light in the "therapeutic window" would enable new approaches for basic research and allow for anticancer phototherapy in hypoxic conditions. This work synthesizes a novel Ru-containing block copolymer for photoactivated chemotherapy in hypoxic tumor environment. The polymer has a hydrophilic poly(ethylene glycol) block and a hydrophobic Ru-containing block, which contains red-light-cleavable (650-680 nm) drug-Ru complex conjugates. The block copolymer self-assembles into micelles, which can be efficiently taken up by cancer cells. Red light induces release of the drug-Ru complex conjugates from the micelles and this process is oxygen independent. The released conjugates inhibit tumor cell growth even in hypoxic tumor environment. Furthermore, the Ru-containing polymer for photoactivated chemotherapy in a tumor-bearing mouse model is applied. Photoactivated chemotherapy of the polymer micelles demonstrates efficient tumor growth inhibition. In addition, the polymer micelles do not cause any toxic side effects to mice during the treatment, demonstrating good biocompatibility of the system to the blood and healthy tissues. The novel red-light-responsive Ru-containing polymer provides a new platform for phototherapy against hypoxic tumors.

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“…[13,16,17] The extension of the dppz ligand with additional rings for example, leads to powerfula nti-tumour properties. [18][19][20] Gaining insight into the manner in which these complexes bind to their target is therefore of importance,w here a deeper structuralk nowledge allows for the superior design of more specific DNA binders. In one recent report, for example, ar apid screening approach was used to identify structural selectivity usingr acemic mixtures of ar ange of halide derivatives of [Ru(bpy) 2 dppz] 2 + ,a nd including the 11-Br analogue of the complex, studied in this work.…”

Section: Introductionmentioning

confidence: 99%

X‐ray Crystal Structures Show DNA Stacking Advantage of Terminal Nitrile Substitution in Ru‐dppz Complexes

McQuaid

Hall

Brazier

et al. 2018

Chemistry A European J

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The new complexes [Ru(TAP) (11-CN-dppz)] , [Ru(TAP) (11-Br-dppz)] and [Ru(TAP) (11,12-diCN-dppz)] are reported. The addition of nitrile substituents to the dppz ligand of the DNA photo-oxidising complex [Ru(TAP) (dppz)] promote π-stacking interactions and ordered binding to DNA, as shown by X-ray crystallography. The structure of Λ-[Ru(TAP) (11-CN-dppz)] with the DNA duplex d(TCGGCGCCGA) shows, for the first time with this class of complex, a closed intercalation cavity with an AT base pair at the terminus. The structure obtained is compared to that formed with the 11-Br and 11,12-dinitrile derivatives, highlighting the stabilization of syn guanine by this enantiomer when the terminal base pair is GC. In contrast the AT base pair has the normal Watson-Crick orientation, highlighting the difference in charge distribution between the two purine bases and the complementarity of the dppz-purine interaction. The asymmetry of the cavity highlights the importance of the purine-dppz-purine stacking interaction.

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A three-in-one-bullet for oesophageal cancer: replication fork collapse, spindle attachment failure and enhanced radiosensitivity generated by a ruthenium(ii) metallo-intercalator

Abstract: [Ru(phen)2(tpphz)]2+ simultaneously inhibits DNA replication, blocks mitosis and enhances DNA-damaging ionising radiation in oesophageal cancer cells.

Cited by 35 publications

References 65 publications

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

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

Red‐Light‐Controlled Release of Drug–Ru Complex Conjugates from Metallopolymer Micelles for Phototherapy in Hypoxic Tumor Environments

X‐ray Crystal Structures Show DNA Stacking Advantage of Terminal Nitrile Substitution in Ru‐dppz Complexes

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