Mechanisms underlying reductant-induced reactive oxygen species formation by anticancer copper(II) compounds

Kowol, Christian R.; Heffeter, Petra; Miklos, Walter; Gille, Lars; Trondl, Robert; Cappellacci, Loredana; Berger, Walter; Keppler, Bernhard K.

doi:10.1007/s00775-011-0864-x

Cited by 130 publications

(104 citation statements)

References 53 publications

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“…However, NAC pre-loading has instead been associated with protective effects against ROS generating copper complexes [24]. In our study, pre-incubation with NAC reduced the cytotoxic activity of VLX60 and therefore the interpretation is that a theoretically expected enhanced cytotoxic activity induced by a reduction of the copper complex extracellularly is outweighed by the antioxidant properties of NAC intracellularly.…”

Section: Discussionmentioning

confidence: 59%

Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity

et al. 2017

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BackgroundThe thiosemicarbazone CD 02750 (VLX50) was recently reported as a hit compound in a phenotype-based drug screen in primary cultures of patient tumor cells. We synthesized a copper complex of VLX50, denoted VLX60, and characterized its antitumor and mechanistic properties.Materials and MethodsThe cytotoxic effects and mechanistic properties of VLX60 were investigated in monolayer cultures of multiple human cell lines, in tumor cells from patients, in a 3-D spheroid cell culture system and in vivo and were compared with those of VLX50.ResultsVLX60 showed ≥ 3-fold higher cytotoxic activity than VLX50 in 2-D cultures and, in contrast to VLX50, retained its activity in the presence of additional iron. VLX60 was effective against non-proliferative spheroids and against tumor xenografts in vivo in a murine model. In contrast to VLX50, gene expression analysis demonstrated that genes associated with oxidative stress were considerably enriched in cells exposed to VLX60 as was induction of reactive oxygen. VLX60 compromised the ubiquitin-proteasome system and was more active in BRAF mutated versus BRAF wild-type colon cancer cells.ConclusionsThe cytotoxic effects of the copper thiosemicarbazone VLX60 differ from those of VLX50 and shows interesting features as a potential antitumor drug, notably against BRAF mutated colorectal cancer.

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Section: Discussionmentioning

confidence: 59%

Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity

et al. 2017

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“…The UPR can be triggered by a wide variety of causes, including accumulation of misfolded/ unfolded proteins, imbalances in ER lipids and glycolipids, changes in the redox environment of the ER caused by ROS, and disruption of Ca 21 homeostasis. Recent studies showed that Cu 21 thiosemicarbazone complexes generate oxidative stress in cell-based assays, whereas the metal-free compounds do not (Hancock et al, 2011;Lovejoy et al, 2011;Kowol et al, 2012). Furthermore, the Cu 21 complex of the thiosemicarbazone NSC 689534 [2-pyridinecarbaldehyde N,N-bis(2-pyridinylmethyl) thiosemicarbazone] was shown to induce ER stress in a ROSdependent manner, whereas the metal-free NSC 689534 does not induce oxidative or ER stress (Hancock et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Triapine and a More Potent Dimethyl Derivative Induce Endoplasmic Reticulum Stress in Cancer Cells

et al. 2013

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Triapine (3-AP; 3-aminopyridine-2-carboxaldehyde thiosemicarbazone), a ribonucleotide reductase inhibitor, has been extensively evaluated in clinical trials in the last decade. This study addresses the role of endoplasmic reticulum (ER) stress in the anticancer activity of 3-AP and the derivative N 4 ,N 4 -dimethyltriapine (3-AP-Me), differing from 3-AP only by dimethylation of the terminal nitrogen. Treatment of colon cancer cells with 3-AP or 3-AP-Me activated all three ER stress pathways (PERK, IRE1a, ATF6) by phosphorylation of eIF2a and upregulation of gene expression of activating transcription factors ATF4 and ATF6. In particular, 3-AP-Me led to an upregulation of the alternatively spliced mRNA variant XBP1 (16-fold). Moreover, 3-AP and 3-AP-Me activated the cellular stress kinases c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases, and inhibition of JNK activity antagonized the cytotoxic effect of both compounds. Subsequent to induction of the unfolded protein response, a significant upregulation of proapoptotic proteins was detected, including the transcription factor CHOP and Bim, an essential factor for ER stress-related apoptosis. In correlation with the higher degree of ER stress after 3-AP-Me treatment, also a more potent depolarization of mitochondrial membranes was found. These data suggest that 3-AP and 3-AP-Me induce apoptosis via ER stress. This was further corroborated by showing that inhibition of protein biosynthesis with cycloheximide prior to 3-AP and 3-AP-Me treatment leads to a significant reduction of the antiproliferative properties of both compounds. Taken together, this study demonstrates that induction of ER stress contributes to the mode of action of 3-AP and that terminal dimethylation leads to an even more pronounced manifestation of this effect.

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“…Fe and Cu complexes have long been predicted as biologically active forms due to intracellular redox cycling potential, and the efforts of synthesizing preformed complexes with Fe, Cu or other metal ions have been pursued in an attempt to improve therapeutic efficacy [5,21–23]. In this study, we have discovered that the simple addition of Cu 2+ to the culture medium abrogates the cytotoxicity of triapine and PT in a 1:1 stoichiometric manner.…”

Section: Introductionmentioning

confidence: 87%

Distinct mechanisms of cell-kill by triapine and its terminally dimethylated derivative Dp44mT due to a loss or gain of activity of their copper(II) complexes

Ishiguro

Lin

Penketh

et al. 2014

Biochemical Pharmacology

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Triapine, currently being evaluated as an antitumor agent in phase II clinical trials, and its terminally dimethylated derivative Dp44mT share the α-pyridyl thiosemicarbazone backbone that functions as ligands for transition metal ions. Yet, Dp44mT is approximately 100-fold more potent than triapine in cytotoxicity assays. The aims of this study were to elucidate the mechanisms underlying their potency disparity and to determine their kinetics of cell-kill in culture to aid in the formulation of their clinical dosing schedules. The addition of Cu2+ inactivated triapine in a 1:1 stoichiometric fashion, while it potentiated the cytotoxicity of Dp44mT. Clonogenic assays after finite-time drug-exposure revealed that triapine produced cell-kill in two phases, one completed within 20 min that caused limited cell-kill, and the other occurring after 16 h of exposure that produced extensive cell-kill. The ribonucleotide reductase inhibitor triapine at 0.4 µM caused immediate complete arrest of DNA synthesis, whereas Dp44mT at this concentration did not appreciably inhibit DNA synthesis. The inhibition of DNA synthesis by triapine was reversible upon its removal from the medium. Cell death after 16 h exposure to triapine paralleled the appearance of phospho-(γ)H2AX, a marker of DNA double-strand breaks induced by collapse of DNA replication forks after prolonged replication arrest. In contrast to triapine, Dp44mT produced robust cell-kill within 1 h in a concentration-dependent manner. The short-term action of both agents was prevented by thiols, indicative of the involvement of reactive oxygen species. The time dependency in the production of cell-kill by triapine should be considered in treatment regimens.

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Mechanisms underlying reductant-induced reactive oxygen species formation by anticancer copper(II) compounds

Cited by 130 publications

References 53 publications

Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity

Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity

Triapine and a More Potent Dimethyl Derivative Induce Endoplasmic Reticulum Stress in Cancer Cells

Distinct mechanisms of cell-kill by triapine and its terminally dimethylated derivative Dp44mT due to a loss or gain of activity of their copper(II) complexes

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