BRCA1 deficiency increases the sensitivity of ovarian cancer cells to auranofin

Oommen, Deepu; Yiannakis, Dennis; Jha, Awadhesh N.

doi:10.1016/j.mrfmmm.2015.11.002

Cited by 23 publications

(27 citation statements)

References 20 publications

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“…Being highly conserved between species [66] we were able to utilise antibodies from differing species to measure γ-H2AX foci induction in marine and freshwater bivalves [67]. Prior to Cu exposure, γ-H2AX response was optimised and validated under in vitro conditions in numerous cells, including haemocytes, gill and digestive gland cells of both the bivalve species using standardized techniques on human cells in our laboratory conditions [48,68].…”

Section: Induction Of γ-H2ax Focimentioning

confidence: 99%

“…DSBs are considered to be most detrimental form of damage, they may be repaired or result in apoptosis and/or mutation. Induction of γ-H2AX is increasingly used as a biomarker in combination with classical and molecular techniques in mammalian systems [48,68,102]. Whilst these techniques are considered to be simple and rapid (fast analysis time) in comparison to many other established methodologies [106], their relative sensitivity and effectiveness have not been compared sufficiently in ecotoxicological studies.…”

Section: Cu Induced Genotoxicity In Gill Cellsmentioning

confidence: 99%

“…The extent of damage in individuals evident at higher levels of biological organisation, subsequent to DNA strand breaks (SBs) is dependent on a range of factors including exposure period, contaminant concentrations, rate of uptake, metabolism, accumulation and the efficiency of repair mechanisms [2]. In recent years, immunostaining techniques such as induction of γ-H2AX foci and 53BP1 have been utilised as sensitive markers of DNA double strand breaks (DSBs) [47][48]. γ-H2AX plays a key role in DNA damage signalling and repair, along with activation of cell-cycle checkpoints and apoptosis [49].…”

Section: Introductionmentioning

confidence: 99%

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Assessing relative sensitivity of marine and freshwater bivalves following exposure to copper: Application of classical and novel genotoxicological biomarkers

Vernon

Jha

2019

Mutation Research/Genetic Toxicology and Environmental Mutagene

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Determination of relative sensitivity of biota following exposures to contaminants including metals is important for environmental protection. Copper (Cu), although biologically essential can be highly toxic to biota if present at higher concentrations in the natural environment. Given its ubiquitous presence within coastal and inland water bodies, we compared Cu-induced genotoxicity in two ecologically important mussel species, the freshwater Dreissena polymorpha (DP) and marine Mytilus galloprovincialis (MG), along with its tissue specific accumulation. Novel biomarker in terms of induction of gamma H2AX (γ-H2AX) foci, along with comet assay and induction of micronuclei (MN) were used to determine DNA damage response (DDR) in these two species following exposure to a range of Cu concentrations (18, 32, 56 µg L-1) for 10 days. Concentration-dependent increases in Cu concentration in gill tissue, as determined by Inductively Coupled Plasma Mass Spectrometry (ICP-MS), were paralleled by a greater degree of genotoxicity. An induction of γ-H2AX foci was present in all Cu exposure concentrations, proving this technique to be a sensitive and suitable biomarker of genotoxicity in bivalves. The multibiomarker approach adopted here suggests firstly that in parallel with MG, which is widely used to assess the health of marine and coastal environment, DP is also suitable representative of inland water bodies, and that there is a similar mechanism of action for the induction of genotoxicity between the two species, following exposure to Cu. Secondly, for genotoxicity assessment a battery of responses could simultaneously be assessed in these two bivalve species. Finally, for adequate protection of the environment it is vital to adopt a multi-biomarker, multi-species approach to determine adverse biological effects to gain a holistic understanding of the real threat posed by contaminants to hydrosphere.

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Section: Induction Of γ-H2ax Focimentioning

confidence: 99%

Section: Cu Induced Genotoxicity In Gill Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Assessing relative sensitivity of marine and freshwater bivalves following exposure to copper: Application of classical and novel genotoxicological biomarkers

Vernon

Jha

2019

Mutation Research/Genetic Toxicology and Environmental Mutagene

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“…Moreover, auranofin is currently undergoing phase 2 clinical trials for re-purposing to treat recurrent epithelial ovarian cancer (https://clinicaltrials.gov/ct2/show/NCT01747798). We have recently reported that genetic depletion of BRCA1 sensitizes ovarian cancer cells to auranofin (10).…”

Section: Introductionmentioning

confidence: 99%

“…Auranofin induces lethal DNA double strand breaks (DSBs) and apoptosis in BRCA1 deficient ovarian cancer cells (10). Anti-oxidant mediated protection of BRCA1 deficient cells suggest that reactive oxygen species (ROS) plays a critical role in auranofin induced DNA damage and apoptosis (10).…”

Section: Introductionmentioning

confidence: 99%

Linking genotoxicity and cytotoxicity with membrane fluidity: A comparative study in ovarian cancer cell lines following exposure to auranofin

Oommen

Dodd

Yiannakis

et al. 2016

Mutation Research/Genetic Toxicology and Environmental Mutagene

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Auranofin, an organogold compound classified as an anti-rheumatic agent is under phase 2 clinical trials for re-purposing to treat recurrent epithelial ovarian cancer. We have reported earlier that Breast cancer 1, early onset (BRCA1) mutant ovarian cancer cells exhibit increased sensitivity to auranofin. BRCA1 is a DNA repair protein whose functional status is critical in the prognosis of ovarian cancer. Apart from DNA repair capability of cancer cells, membrane fluidity is also implicated in modulating resistance to chemotherapeutics. We report here that membrane fluidity influences the sensitivity of ovarian cancer cell lines, OVCAR5 and IGROV1, to auranofin. Electron spin resonance (ESR) analysis revealed a more fluidized membrane in IGROV1 compared to OVCAR5. Interestingly, IGROV1 cells were more sensitive to auranofin induced cytotoxicity than OVCAR5. In comparison to OVCAR5, IGROV1 cells also exhibited an increased number of DNA double strand breaks (DSBs) upon auranofin treatment as assessed by 53BP1 immunostaining. Furthermore, correlation analysis demonstrated a strong positive correlation (r=0.856) between membrane fluidity and auranofin sensitivity in these cell lines. Auranofin-treated IGROV1 cells also exhibited increased cellular oxidation and apoptosis. Anti-oxidant, N-acetyl cysteine (NAC) inhibited the cellular oxidation and apoptosis in auranofin-treated ovarian cancer cells suggesting reactive oxygen species (ROS) mediate the anti-cancer properties of auranofin. Overall, our study suggests that auranofin mediates its cytotoxicity via ROS production in ovarian cancer cells which correlates positively with membrane fluidity.

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An Artemisinin‐Derivative–(NHC)Gold(I) Hybrid with Enhanced Cytotoxicity through Inhibition of NRF2 Transcriptional Activity

et al. 2020

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A family of hybrid complexes combining two biologically active motifs, an artemisinin derivative and a cationic bis(NHC)‐gold(I) unit, has been synthesized. One of these complexes, 2 a, has been analyzed by single‐crystal X‐ray diffraction. 2 a shows strong anticancer activities on a large panel of human cancer cell models (prostate, breast, lung, liver, bladder, bone, acute and chronic myeloid leukemias) with GI50 values in the nm range, together with a high selectivity. An original and distinctive mechanism of action, that is, through inhibition of the redox antioxidant NRF2 transcription factor (strongly associated with aggressiveness and resistance to cancer therapies) has been evidenced. 2 a could remarkably sensitize to sorafenib in HepG2 liver cells, in which dysregulated NRF2 signaling is linked to primary and acquired drug resistance. 2 a also inhibited NF‐κB and HIF transcriptional activities, which are also associated with progression and resistance in cancer. Our findings provide evidence that hybrid (NHC)gold(I) compounds represent a new class of organometallic hybrid molecules that may yield new therapeutic agents.

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BRCA1 deficiency increases the sensitivity of ovarian cancer cells to auranofin

Cited by 23 publications

References 20 publications

Assessing relative sensitivity of marine and freshwater bivalves following exposure to copper: Application of classical and novel genotoxicological biomarkers

Assessing relative sensitivity of marine and freshwater bivalves following exposure to copper: Application of classical and novel genotoxicological biomarkers

Linking genotoxicity and cytotoxicity with membrane fluidity: A comparative study in ovarian cancer cell lines following exposure to auranofin

An Artemisinin‐Derivative–(NHC)Gold(I) Hybrid with Enhanced Cytotoxicity through Inhibition of NRF2 Transcriptional Activity

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