- Reactions of Auranofin and Its Pseudohalide Derivatives with Serum Albumin Investigated through ESI-Q-TOF MS. [Journal Article]
- ICInorg Chem 2018 Aug 15
- The reactions of auranofin and three pseudohalide derivatives with bovine serum albumin were explored by ESI-Q-TOF mass spectrometry; a detailed molecular description of the resulting adducts is achi...
The reactions of auranofin and three pseudohalide derivatives with bovine serum albumin were explored by ESI-Q-TOF mass spectrometry; a detailed molecular description of the resulting adducts is achieved revealing even subtle differences in reactivity within this series of gold(I) complexes. Our study shows that this kind of investigative approach, formerly applied to the interactions of metal-based drugs with small model proteins of MW 10-15 kDa, e.g., cytochrome c and lysozyme, may now be extended with success to far larger proteins such as serum albumin (MW 66 kDa).
- Auranofin Enhances Ibrutinib's Anticancer Activity in EGFR-Mutant Lung Adenocarcinoma. [Journal Article]
- MCMol Cancer Ther 2018 Jul 31
- We previously found that ibrutinib has anticancer activity in EGFR-mutant non-small cell lung cancer (NSCLC). One of our recent studies showed that auranofin, a gold complex that has been used to tre...
We previously found that ibrutinib has anticancer activity in EGFR-mutant non-small cell lung cancer (NSCLC). One of our recent studies showed that auranofin, a gold complex that has been used to treat rheumatoid arthritis, inhibited the PI3K/AKT/mTOR pathway and promoted apoptosis in some NSCLC cells. Because the PI3K/AKT/mTOR pathway is one of the major downstream pathways of EGFR, we hypothesized that ibrutinib's activity might be enhanced by combination therapy with auranofin in NSCLC cells. To this end, we examined ibrutinib's dose responses in EGFR-mutant H1975, PC9 and H1650 cells and in EGFR-wild type Calu3 and H460 cells in the presence or absence of auranofin. While low concentrations of auranofin alone demonstrated mild anticancer activities, its presence dramatically enhanced ibrutinib's activity in H1975, PC9 and H1650 cells (IC50 value reduced 10 - 100 fold), but had only mild effect on Calu3 and H460 cells, demonstrating that ibrutinib's anti-EGFR activity is enhanced when it is combined with auranofin. A mechanistic analysis revealed that ibrutinib alone induced dramatic inhibition of the MEK/ERK pathway in both H1975 and H1650 cells, while auranofin alone inhibited the AKT/mTOR pathway. The combination of ibrutinib and auranofin led to dramatically enhanced inhibition of the expression or phosphorylation of multiple key nodes in the AKT/mTOR and MEK/ERK pathways in both cell lines. In mice, the combination of ibrutinib and auranofin significantly suppressed the growth of H1975 xenografted tumors without inducing obvious toxic effects. Our results demonstrate the feasibility of improving ibrutinib's anti-EGFR activity for NSCLC using combination therapy with auranofin.
- The Thioredoxin Reductase Inhibitor Auranofin Induces Heme Oxygenase-1 in Lung Epithelial Cells Via Nrf2-dependent Mechanisms. [Journal Article]
- AJAm J Physiol Lung Cell Mol Physiol 2018 Jul 19
- Thioredoxin reductase-1 (TXNRD1) inhibition effectively activates nuclear factor (erythroid-derived 2)-like 2 (Nrf2) responses and attenuates lung injury in acute respiratory distress syndrome (ARDS)...
Thioredoxin reductase-1 (TXNRD1) inhibition effectively activates nuclear factor (erythroid-derived 2)-like 2 (Nrf2) responses and attenuates lung injury in acute respiratory distress syndrome (ARDS) and bronchopulmonary dysplasia (BPD) models. Upon TXNRD1 inhibition, heme oxygenase-1 (HO-1) is disproportionally increased compared with Nrf2 target NADPH quinone oxidoreductase-1 (NQO1). HO-1 has been investigated as a potential therapeutic target in both ARDS and BPD. TXNRD1 is predominantly expressed in airway epithelial cells; however, the mechanism of HO-1 induction by TXNRD1 inhibitors is unknown. We tested the hypothesis that TXNRD1 inhibition induces HO-1 via Nrf2-dependent mechanisms. Wild type (WT), Nrf2KO1.3, and Nrf2KO2.2 cells were morphologically indistinguishable indicating that Nrf2 can be deleted from murine transformed club cells (mtCCs) using CRISPR/Cas9 gene editing. Hemin, a Nrf2-independent HO-1 inducing agent, significantly increased HO-1 expression in WT, Nrf2KO1.3, and Nrf2KO2.2. Auranofin (AFN, 0.5 µM) inhibited TXNRD1 activity by 50% and increased Nqo1 and Hmox1 mRNA levels by 6-fold and 24-fold, respectively in WT cells. Despite similar levels of TXNRD1 inhibition, Nqo1 mRNA levels were not different between control and AFN-treated Nrf2KO1.3 and Nrf2KO2.2. AFN slightly increased Hmox1 mRNA levels in Nrf2KO1.3 and Nrf2KO2.2 cells compared with controls. AFN failed to increase HO-1 protein in Nrf2KO1.3 and Nrf2KO2.2 compared with a 36-fold increase in WT mtCCs. Our data indicate that Nrf2 is the primary mechanism by which TXNRD1 inhibitors increase HO-1 in lung epithelia. Future studies will use ARDS and BPD models to define the role of HO-1 in attenuation of lung injury by TXNRD1 inhibitors.
- Evaluating New Compounds to Treat Burkholderia pseudomallei Infections. [Journal Article]
- FCFront Cell Infect Microbiol 2018; 8:210
- Burkholderia pseudomallei is the causative agent of melioidosis, a disease that requires long-term treatment regimens with no assurance of bacterial clearance. Clinical isolates are intrinsically res...
Burkholderia pseudomallei is the causative agent of melioidosis, a disease that requires long-term treatment regimens with no assurance of bacterial clearance. Clinical isolates are intrinsically resistant to most antibiotics and in recent years, isolates have been collected that display resistance to frontline drugs. With the expanding global burden of B. pseudomallei, there is a need to identify new compounds or improve current treatments to reduce risk of relapse. Using the Pathogen Box generated by Medicines for Malaria Venture, we screened a library of 400 compounds for bacteriostatic or bactericidal activity against B. pseudomallei K96243 and identified seven compounds that exhibited inhibitory effects. New compounds found to have function against B. pseudomallei were auranofin, rifampicin, miltefosine, MMV688179, and MMV688271. An additional two compounds currently used to treat melioidosis, doxycycline and levofloxacin, were also identified in the screen. We determined that the minimal inhibitory concentrations (MIC) for levofloxacin, doxycycline, and MMV688271 were below 12 μg/ml for 5 strains of B. pseudomallei. To assess persister frequency, bacteria were exposed to 100x MIC of each compound. Auranofin, MMV688179, and MMV688271 reduced the bacterial population to an average of 4.53 × 10-6% compared to ceftazidime, which corresponds to 25.1% survival. Overall, our data demonstrates that auranofin, MMV688197, and MMV688271 have the potential to become repurposed drugs for treating melioidosis infections and the first evidence that alternative therapeutics can reduce B. pseudomallei persistence.
- Drugs and Lactation Database (LactMed) [BOOK]
- BOOKNational Library of Medicine (US): Bethesda (MD)
- Excretion of gold into milk after auranofen has not been studied. Case reports with other gold salts indicate that gold appears in milk in small quantities and at least a little of it is absorbed bec...
Excretion of gold into milk after auranofen has not been studied. Case reports with other gold salts indicate that gold appears in milk in small quantities and at least a little of it is absorbed because it is detectable in the infant's urine. No convincing cases of toxicity have been reported. Opinions of authors of review articles vary from recommending avoidance to allowing use. Monitoring for possible adverse effects in the breastfed infant would seem prudent.
- A Quantitative Chemoproteomic Platform to Monitor Selenocysteine Reactivity within a Complex Proteome. [Journal Article]
- CCCell Chem Biol 2018 Jun 12
- Mammalian selenocysteine (Sec)-containing proteins, selenoproteins, are important to (patho)physiological processes, including redox homeostasis. Sec residues have been recalcitrant to mass spectrome...
Mammalian selenocysteine (Sec)-containing proteins, selenoproteins, are important to (patho)physiological processes, including redox homeostasis. Sec residues have been recalcitrant to mass spectrometry-based chemoproteomic methods that enrich for reactive cysteine (Cys) residues with electrophilic chemical probes, despite confirmed reactivity of Sec with these electrophiles. Highly abundant Cys peptides likely suppress low-abundant Sec peptides. By exploiting the decreased pKa of Sec relative to Cys, we have developed a chemoproteomic platform that relies on low pH (pH 5.75) electrophile labeling, reducing Cys reactivity and enhancing identification of Sec-containing peptides across mouse tissues and cell lines. The utility of this Sec-profiling platform is underscored by evaluation of the selectivity of auranofin, an inhibitor of the selenoprotein, thioredoxin reductase, against both reactive Cys- and Sec-containing proteins. Platform limitations pertain to the non-physiological low-pH conditions that could perturb protein structure and function. Future work necessitates the discovery of Sec-selective electrophiles that function at physiological pH.
- Antiproliferative effects of two gold(I)-N-heterocyclic carbene complexes in A2780 human ovarian cancer cells: a comparative proteomic study. [Journal Article]
- OOncotarget 2018 Jun 15; 9(46):28042-28068
- Au(NHC) and Au(NHC)2, i.e. a monocarbene gold(I) complex and the corresponding bis(carbene) complex, are two structurally related compounds, endowed with cytotoxic properties against several cancer c...
Au(NHC) and Au(NHC)2, i.e. a monocarbene gold(I) complex and the corresponding bis(carbene) complex, are two structurally related compounds, endowed with cytotoxic properties against several cancer cell lines. Herein, we explore the molecular and cellular mechanisms at the basis of their cytotoxicity in A2780 human ovarian cancer cells. Through a comparative proteomic analysis, we demonstrated that the number of modulated proteins is far larger in Au(NHC)2-treated than in Au(NHC)-treated A2780 cells. Both gold compounds mainly affected proteins belonging to the following functional classes: protein synthesis, metabolism, cytoskeleton and stress response and chaperones. Particularly, Au(NHC)2 gave rise to an evident upregulation of several glycolytic enzymes. Moreover, only Au(NHC)2 triggered a net impairment of respiration and a metabolic shift towards glycolysis, suggesting that mitochondria are relevant cellular targets. We also found that both carbenes, similarly to the gold(I) compound auranofin, caused a strong inhibition of the seleno-enzyme thioredoxin reductase (TrxR). In conclusion, we highlighted that coordination of two carbene ligands to the same gold(I) center greatly enhances the antiproliferative effects of the resulting compound in comparison to the monocarbene derivative. Moreover, TrxR inhibition and metabolic impairment seem to play a major role in the Au(NHC)2 cytotoxicity. Overall, these antiproliferative effects were also confirmed on other two human ovarian cancer cell lines (i.e. SKOV3 and IGROV1).
- Viability Screen of LOPAC1280 Reveals Phosphorylation Inhibitor Auranofin as Potent Inhibitor of Blastocystis ST1, ST4 and ST7 Isolates. [Journal Article]
- AAAntimicrob Agents Chemother 2018 Jun 04
- Blastocystis is an enteric parasite with extensive global prevalence. Studies have linked infection with this protist with a variety of gastrointestinal disorders, including irritable bowel syndrome....
Blastocystis is an enteric parasite with extensive global prevalence. Studies have linked infection with this protist with a variety of gastrointestinal disorders, including irritable bowel syndrome. Due to the polymorphic nature of Blastocystis, studies on the parasite could be complicated as results can be easily misinterpreted. Metronidazole is the commonly prescribed drug for Blastocystis infection although there have been increasing reports of drug resistance. Hence, there is a need to identify alternative drugs to eliminate Blastocystis infection. In this study, LOPAC1280 was screened and drugs that can decrease the viability of three Blastocystis isolates in cultures were identified. Using apoptosis assay and imaging flow cytometry, phenotypic changes in Blastocystis cells after treatment were also analyzed to obtain insights into the possible mechanism of action of these drugs. Three drugs - diphenyleneiodonium chloride, auranofin and BIX 01294 trihydrochloride hydrate, were effective against all three isolates tested. Repurposing of these drugs for Blastocystis treatment could be a way of combatting metronidazole resistance relatively quickly and at a lower cost.
- Repurposing auranofin as an intestinal decolonizing agent for vancomycin-resistant enterococci. [Journal Article]
- SRSci Rep 2018 May 29; 8(1):8353
- Multidrug-resistant enterococcal pathogens, especially vancomycin-resistant enterococci (VRE), are among the pathogens that require new antibiotic innovation. The colonization of the gut represents a...
Multidrug-resistant enterococcal pathogens, especially vancomycin-resistant enterococci (VRE), are among the pathogens that require new antibiotic innovation. The colonization of the gut represents a major pathway by which VRE can cause infection and spread to other patients. In the current study, auranofin (FDA-approved rheumatoid arthritis drug) is evaluated for its potential use as a decolonizing agent for VRE. Auranofin was found to exert potent antimicrobial activity against a wide range of enterococcal clinical isolates with a minimum inhibitory concentration of 1 μg/mL. No resistant mutants could be developed against auranofin over the course of 14 passages. Auranofin was also found to exert potent anti-biofilm activity against VRE. Auranofin was superior to linezolid, the drug of choice for VRE infection treatment, in the in vivo mouse model. Auranofin significantly reduced the VRE burden in feces, cecum, and ileum contents after 8 days of treatment. Accordingly, this study provides valuable evidence that auranofin has significant promise as a novel gastrointestinal decolonizing agent for VRE.
New Search Next
- Mutant p53 tunes the NRF2-dependent antioxidant response to support survival of cancer cells. [Journal Article]
- OOncotarget 2018 Apr 17; 9(29):20508-20523
- NRF2 (NFE2L2) is one of the main regulators of the antioxidant response of the cell. Here we show that in cancer cells NRF2 targets are selectively upregulated or repressed through a mutant p53-depen...
NRF2 (NFE2L2) is one of the main regulators of the antioxidant response of the cell. Here we show that in cancer cells NRF2 targets are selectively upregulated or repressed through a mutant p53-dependent mechanism. Mechanistically, mutant p53 interacts with NRF2, increases its nuclear presence and resides with NRF2 on selected ARE containing gene promoters activating the transcription of a specific set of genes while leading to the transcriptional repression of others. We show that thioredoxin (TXN) is a mutant p53-activated NRF2 target with pro-survival and pro-migratory functions in breast cancer cells under oxidative stress, while heme oxygenase 1 (HMOX1) is a mutant p53-repressed target displaying opposite effects. A gene signature of NRF2 targets activated by mutant p53 shows a significant association with bad overall prognosis and with mutant p53 status in breast cancer patients. Concomitant inhibition of thioredoxin system with Auranofin and of mutant p53 with APR-246 synergizes in killing cancer cells expressing p53 gain-of-function mutants.