Effects of frequently applied carbon monoxide releasing molecules (CORMs) in typical CO-sensitive model systems – A comparative in vitro study

Stucki, David; Krahl, Heide; Walter, Moritz; Steinhausen, Julia; Hommel, Katrin; Brenneisen, Peter; Stahl, Wilhelm

doi:10.1016/j.abb.2020.108383

Cited by 31 publications

(20 citation statements)

References 39 publications

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“…These results [67] show that the ruthenium-based CORM by-product, iCORM-2, is itself cytotoxic and suggest that the accumulation of iCORM-2 would limit clinical applications of the ruthenium-based CORMs. The validity of using iCORM-2 was also dismissed by [68] who showed that it inhibited activity of recombinant cytochrome P-450. These authors also demonstrated that both CORM-2 and CORM-3 elicited a rapid depletion of oxygen in respirometry which was detected in the medium, even when no cells were present [68].…”

Section: Discussionmentioning

confidence: 99%

“…The validity of using iCORM-2 was also dismissed by [68] who showed that it inhibited activity of recombinant cytochrome P-450. These authors also demonstrated that both CORM-2 and CORM-3 elicited a rapid depletion of oxygen in respirometry which was detected in the medium, even when no cells were present [68]. Thus, several recent studies cast doubt on the proposal that CORM-2 acts solely as a CO releaser.…”

Section: Discussionmentioning

confidence: 99%

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‘Carbon-Monoxide-Releasing Molecule-2 (CORM-2)’ Is a Misnomer: Ruthenium Toxicity, Not CO Release, Accounts for Its Antimicrobial Effects

et al. 2021

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Carbon monoxide (CO)-releasing molecules (CORMs) are used to deliver CO, a biological ‘gasotransmitter’, in biological chemistry and biomedicine. CORMs kill bacteria in culture and in animal models, but are reportedly benign towards mammalian cells. CORM-2 (tricarbonyldichlororuthenium(II) dimer, Ru2Cl4(CO)6), the first widely used and commercially available CORM, displays numerous pharmacological, biochemical and microbiological activities, generally attributed to CO release. Here, we investigate the basis of its potent antibacterial activity against Escherichia coli and demonstrate, using three globin CO sensors, that CORM-2 releases negligible CO (<0.1 mol CO per mol CORM-2). A strong negative correlation between viability and cellular ruthenium accumulation implies that ruthenium toxicity underlies biocidal activity. Exogenous amino acids and thiols (especially cysteine, glutathione and N-acetyl cysteine) protected bacteria against inhibition of growth by CORM-2. Bacteria treated with 30 μM CORM-2, with added cysteine and histidine, exhibited no significant loss of viability, but were killed in the absence of these amino acids. Their prevention of toxicity correlates with their CORM-2-binding affinities (Cys, Kd 3 μM; His, Kd 130 μM) as determined by 1H-NMR. Glutathione is proposed to be an important intracellular target of CORM-2, with CORM-2 having a much higher affinity for reduced glutathione (GSH) than oxidised glutathione (GSSG) (GSH, Kd 2 μM; GSSG, Kd 25,000 μM). The toxicity of low, but potent, levels (15 μM) of CORM-2 was accompanied by cell lysis, as judged by the release of cytoplasmic ATP pools. The biological effects of CORM-2 and related CORMs, and the design of biological experiments, must be re-examined in the light of these data.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

‘Carbon-Monoxide-Releasing Molecule-2 (CORM-2)’ Is a Misnomer: Ruthenium Toxicity, Not CO Release, Accounts for Its Antimicrobial Effects

et al. 2021

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“…CORM-401 was freshly dissolved in PBS (5 mM) and aliquots were stored at −20 • C. The compound is stable under these conditions [23]. CO release from CORM-401 occurs only in the presence of CO acceptors, such as heme proteins [24,25].…”

Section: Handling Of Corm-401 and Icorm-401mentioning

confidence: 99%

“…CORMs provide a continuous exposure of cells to standardized amounts of CO (in contrast to the application of gaseous CO). From the number of different CORMs, CORM-401 was already shown to be a suitable CO delivery system, especially for studies on the impact of CO on energy metabolism [23]. CORM-401 releases CO only in the close presence of suitable CO acceptors (heme proteins) [24] and therefore ensures controlled intracellular availability of the signaling molecule.…”

Section: Introductionmentioning

confidence: 99%

Endogenous Carbon Monoxide Signaling Modulates Mitochondrial Function and Intracellular Glucose Utilization: Impact of the Heme Oxygenase Substrate Hemin

et al. 2020

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Stress-inducible heme oxygenase-1 (HO-1) catalyzes the oxidative cleavage of heme yielding biliverdin, ferrous iron, and carbon monoxide (CO). Heme oxygenase activity has been attributed to antioxidant defense via the redox cycling system of biliverdin and bilirubin. There is increasing evidence that CO is a gaseous signaling molecule and plays a role in the regulation of energy metabolism. Inhibitory effects of CO on the respiratory chain are well established, but the implication of such a process on the cellular stress response is not well understood. By means of extracellular flux analyses and isotopic tracing, we studied the effects of CO, either released from the CO donor CORM-401 or endogenously produced by heme oxygenases, on the respiratory chain and glucose metabolism. CORM-401 was thereby used as a tool to mimic endogenous CO production by heme oxygenases. In the long term (>60 min), CORM-401-derived CO exposure inhibited mitochondrial respiration, which was compensated by increased glycolysis accompanied by a loss of the ATP production rate and an increase in proton leakage. This effect pattern was likewise observed after endogenous CO production by heme oxygenases. However, in the present setting, these effects were only observed when sufficient substrate for heme oxygenases (hemin) was provided. Modulation of the HO-1 protein level was less important. The long-term influence of CO on glucose metabolism via glycolysis was preceded by a short-term response (<30 min) of the cells to CO. Stable isotope-labeling experiments and metabolic flux analysis revealed a short-term shift of glucose consumption from glycolysis to the pentose phosphate pathway (PPP) along with an increase in reactive oxygen species (ROS) generation. Overall, we suggest that signaling by endogenous CO stimulates the rapid formation of reduction equivalents (NADPH) via the PPP, and plays an additional role in antioxidant defense, e.g., via feed-forward stimulation of the bilirubin/biliverdin redox cycling system.

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“…These metalimmobilized carbonyls have played a very significant role in understanding CO physiology and in demonstrating pharmacological efficacy in various animal models. However, in recent years, there have been discussions of what roles that transition metal plays in some of the observed biological effects with important questions raised as to whether the observed effects can be solely attributed to CO; how much CO is released under physiological conditions, the ability for the CO-RMs to react with proteins and undergo/facilitate other reactions; and the cytotoxicity and other biological effects of the metal component [7,[26][27][28][36][37][38]. A recent study also showed that the widely reported effect of ruthenium-based CO-RMs (CORM-2, -3) on coagulation [39] is via a CO-independent mechanism, suggesting the importance of looking at the metal carrier in examining the effects of CO-RMs [40].…”

Section: Introductionmentioning

confidence: 99%

Towards “CO in a pill”: Pharmacokinetic studies of carbon monoxide prodrugs in mice

Wang

Yang

Pan

et al. 2020

Journal of Controlled Release

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Effects of frequently applied carbon monoxide releasing molecules (CORMs) in typical CO-sensitive model systems – A comparative in vitro study

Cited by 31 publications

References 39 publications

‘Carbon-Monoxide-Releasing Molecule-2 (CORM-2)’ Is a Misnomer: Ruthenium Toxicity, Not CO Release, Accounts for Its Antimicrobial Effects

‘Carbon-Monoxide-Releasing Molecule-2 (CORM-2)’ Is a Misnomer: Ruthenium Toxicity, Not CO Release, Accounts for Its Antimicrobial Effects

Endogenous Carbon Monoxide Signaling Modulates Mitochondrial Function and Intracellular Glucose Utilization: Impact of the Heme Oxygenase Substrate Hemin

Towards “CO in a pill”: Pharmacokinetic studies of carbon monoxide prodrugs in mice

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