Antiproliferative effect of gold(I) compound auranofin through inhibition of STAT3 and telomerase activity in MDA-MB 231 human breast cancer cells

Kim, Nam Hoon; Park, Hyo-Jung; Oh, Mi-Kyung; Kim, Insook

doi:10.5483/bmbrep.2013.46.1.123

Cited by 71 publications

(52 citation statements)

References 27 publications

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“…AUR inhibits thioredoxin reductase (TrxR), a major cellular anti-oxidant protein that is a component of the cellular Trx system [9]. AUR has been shown to induce apoptotic death of multiple human tumors including breast cancer [10], ovarian cancer [11], multiple myeloma (MM) [12], and chronic lymphocytic leukemia (CLL) [13]. …”

Section: Introductionmentioning

confidence: 99%

Dual targeting of the thioredoxin and glutathione antioxidant systems in malignant B cells: A novel synergistic therapeutic approach

Kiebala

Skalska

Casulo

et al. 2015

Experimental Hematology

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B-cell malignancies are a common type of cancer. One approach to cancer therapy is to either increase oxidative stress or inhibit the stress response systems on which cancer cells rely. In this study, we combined non-toxic concentrations of Auranofin (AUR), an inhibitor of the thioredoxin (Trx) system, with non-toxic concentrations of buthionine-sulfoximine (BSO), a compound that reduces intracellular glutathione (GSH) levels, and investigated the effect of this drug combination on multiple pathways critical for malignant B-cell survival. AUR interacted synergistically with BSO at low concentrations to trigger death in multiple malignant B-cell lines and primary mantle cell lymphoma (MCL) cells. Additionally, there was less toxicity toward normal B-cells. Low AUR concentrations inhibited Trx reductase (TrxR) activity, an effect significantly increased by BSO co-treatment. TrxR over-expression partially reversed AUR+BSO toxicity. Interestingly, the combination of AUR+BSO inhibited NF-κB signaling. Moreover, synergistic cell death induced by this regimen was attenuated in cells over-expressing NF-κB proteins, arguing for a functional role for NF-κB inhibition in AUR+BSO-mediated cell death. Together, these findings suggest that AUR+BSO synergistically induce malignant B-cell death, a process mediated by dual inhibition of TrxR and NF-κB, and such an approach warrants further investigation in B-cell malignancies.

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Section: Introductionmentioning

confidence: 99%

Dual targeting of the thioredoxin and glutathione antioxidant systems in malignant B cells: A novel synergistic therapeutic approach

Kiebala

Skalska

Casulo

et al. 2015

Experimental Hematology

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“…The complex, which was initially developed as an anti-rheumatic agent, recently had its potentiality as an anticancer agent well investigated [9]. As it is readily metabolized by thiol biomolecules, the coordinated ligands are mostly rendered impotent before the target enzyme is reached [10].…”

Section: Introductionmentioning

confidence: 99%

Gold (I) N-heterocyclic carbene complex inhibits mouse melanoma growth by p53 upregulation

et al. 2014

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BackgroundCancer treatment using gold (I) complexes is becoming popular. In this study, a gold (I) N-heterocyclic complex designated as complex 3 was synthesized, its cytotoxicity was examined, and its anti-melanoma activity was evaluated in vitro and in vivo.MethodsViability of cancer cells was determined by MTT assay upon treatment with various concentrations of a gold (I) N-heterocyclic carbene complex (complex 3) in a dose and time dependent manner. Mouse melanoma cells B16F10 were selected for further apoptotic studies, including flowcytometric analysis of annexin binding, cell cycle arrest, intracellular ROS generation and loss in the mitochondrial membrane potential. ELISA based assays were done for caspase activities and western blots for determining the expression of various survival and apoptotic proteins. Immunocytology was performed to visualize the translocation of p53 to the nucleus. B16F10 cells were inoculated into mice and post tumor formation, complex 3 was administered. Immunohistology was performed to determine the expressions of p53, p21, NF-κB (p65 and p50), MMP-9 and VEGF. Student’s t test was used for determining statistical significance. The survival rate data were analyzed by Kaplan-Meier plots.ResultsComplex 3 markedly inhibited the growth of HCT 116, HepG2, and A549, and induced apoptosis in B16F10 cells with nuclear condensation, DNA fragmentation, externalization of phosphatidylserine, activation of caspase 3 and caspase 9, PARP cleavage, downregulation of Bcl-2, upregulation of Bax, cytosolic cytochrome c elevation, ROS generation, and mitochondrial membrane potential loss indicating the involvement of an intrinsic mitochondrial death pathway. Further, upregulation of p53, p-p53 (ser 15) and p21 indicated the role of p53 in complex 3 mediated apoptosis. The complex reduced tumor size, and caused upregulation of p53 and p21 along with downregulation of NF-κB (p65 and p50), VEGF and MMP-9. These results suggest that it induced anti-melanoma effect in vitro and in vivo by modulating p53 and other apoptotic factors.ConclusionsThe gold (I) N-heterocyclic carbene complex (C22H26N6AuO2PF6) designated as complex 3 induced ROS and p53 dependent apoptosis in B16F10 cells involving the mitochondrial death pathway along with suppression of melanoma tumor growth by regulating the levels of pro and anti apoptotic factors (p53, p21, NF-κB, VEGF and MMP-9).

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“…[1] As an example,s everal cytotoxic gold(I) N-heterocyclic carbene (NHC) complexes are potent inhibitors of the mitochondrial selenoenzyme thioredoxin reductase,w hich is involved in the maintenance of the intracellular redox balance. [11] Small molecules that are able to bind and block telomerase generally manifest remarkable anticancer properties.M oreover, G-quadruplex binding properties correlate well with antitelomerase activity. [2] Thel atter hypothesis (that is,apronounced antitelomerase activity) emerges distinctly from previous studies on auranofin.…”

mentioning

confidence: 99%

“…[2] Thel atter hypothesis (that is,apronounced antitelomerase activity) emerges distinctly from previous studies on auranofin. [11] Small molecules that are able to bind and block telomerase generally manifest remarkable anticancer properties.M oreover, G-quadruplex binding properties correlate well with antitelomerase activity. [12] G-quadruplexes (also known as G4) are nucleic acid sequences,rich in guanines,capable of forming acharacteristic four-stranded fold.…”

mentioning

confidence: 99%

Determinants for Tight and Selective Binding of a Medicinal Dicarbene Gold(I) Complex to a Telomeric DNA G‐Quadruplex: a Joint ESI MS and XRD Investigation

et al. 2016

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The dicarbene gold(I) complex [Au(9-methylcaffein-8-ylidene) 2 ]BF 4 is an exceptional organometallic compound of profound interest as ap rospective anticancer agent. This gold(I) complex was previously reported to be highly cytotoxic toward various cancer cell lines in vitro and behaves as aselective G-quadruplex stabilizer.Interactions of the gold complex with various telomeric DNAm odels have been analyzed by ac ombined ESI MS and X-ray diffraction (XRD) approach.ESI MS measurements confirmed formation of stable adducts between the intact gold(I) complex and Tel23 DNAs equence.T he crystal structure of the adduct formed between [Au(9-methylcaffein-8-ylidene) 2 ] + and Tel2 3D NA G-quadruplex was solved. Tel2 3maintains ac haracteristic propeller conformation while binding three gold(I) dicarbene moieties at two distinct sites.S tacking interactions appear to drive noncovalent binding of the gold(I) complex. The structural basis for tight gold(I) complex/G-quadruplex recognition and its selectivity are described.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under http://dx.

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Antiproliferative effect of gold(I) compound auranofin through inhibition of STAT3 and telomerase activity in MDA-MB 231 human breast cancer cells

Cited by 71 publications

References 27 publications

Dual targeting of the thioredoxin and glutathione antioxidant systems in malignant B cells: A novel synergistic therapeutic approach

Dual targeting of the thioredoxin and glutathione antioxidant systems in malignant B cells: A novel synergistic therapeutic approach

Gold (I) N-heterocyclic carbene complex inhibits mouse melanoma growth by p53 upregulation

Determinants for Tight and Selective Binding of a Medicinal Dicarbene Gold(I) Complex to a Telomeric DNA G‐Quadruplex: a Joint ESI MS and XRD Investigation

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