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  • 1
    Language: English
    In: Scientific reports, 2021-01-08, Vol.11 (1), p.207-207
    Description: The long-standing perception of Protein Kinase C (PKC) as a family of oncoproteins has increasingly been challenged by evidence that some PKC isoforms may act as tumor suppressors. To explore the hypothesis that activation, rather than inhibition, of these isoforms is critical for anticancer activity, we isolated and characterized a family of 16 novel phorboids closely-related to tigilanol tiglate (EBC-46), a PKC-activating epoxytigliane showing promising clinical safety and efficacy for intratumoral treatment of cancers. While alkyl branching features of the C12-ester influenced potency, the 6,7-epoxide structural motif and position was critical to PKC activation in vitro. A subset of the 6,7-epoxytiglianes were efficacious against established tumors in mice; which generally correlated with in vitro activation of PKC. Importantly, epoxytiglianes without evidence of PKC activation showed limited antitumor efficacy. Taken together, these findings provide a strong rationale to reassess the role of PKC isoforms in cancer, and suggest in some situations their activation can be a promising strategy for anticancer drug discovery.
    Subject(s): Antitumor activity ; Cancer ; Isoforms ; Kinases ; Mechanism of action ; Natural products ; Protein kinase C ; Tumors
    ISSN: 2045-2322
    E-ISSN: 2045-2322
    Source: Nature Open Access
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 2
    Language: English
    In: PloS one, 2014, Vol.9 (3), p.e90219-e90219
    Description: Disruption of the Setx gene, defective in ataxia oculomotor apraxia type 2 (AOA2) leads to the accumulation of DNA/RNA hybrids (R-loops), failure of meiotic recombination and infertility in mice. We report here the presence of R-loops in the testes from other autosomal recessive ataxia mouse models, which correlate with fertility in these disorders. R-loops were coincident in cells showing high basal levels of DNA double strand breaks and in those cells undergoing apoptosis. Depletion of Setx led to high basal levels of R-loops and these were enhanced further by DNA damage both in vitro and in vivo in tissues with proliferating cells. There was no evidence for accumulation of R-loops in the brains of mice where Setx, Atm, Tdp1 or Aptx genes were disrupted. These data provide further evidence for genome destabilization as a consequence of disrupted transcription in the presence of DNA double strand breaks arising during DNA replication or recombination. They also suggest that R-loop accumulation does not contribute to the neurodegenerative phenotype in these autosomal recessive ataxias.
    Subject(s): Accumulation ; Analysis ; Animal models ; Animal tissues ; Animals ; Apoptosis ; Ataxia ; Bioinformatics ; Biology ; Biology and Life Sciences ; Brain ; Brain - metabolism ; Brain research ; Cell cycle ; Cell Proliferation ; Cognitive ability ; Computer engineering ; Data analysis ; Defects ; Deoxyribonucleic acid ; Destabilization ; Disease Models, Animal ; DNA ; DNA biosynthesis ; DNA Damage ; DNA repair ; DNA replication ; Fertility ; Gene expression ; Genes ; Genetic aspects ; Genetic transcription ; Genomes ; Genomics ; Germ Cells - metabolism ; Hybrids ; Infertility ; Infertility - genetics ; Ionizing radiation ; Laboratories ; Male ; Medical research ; Medicine and Health Sciences ; Meiosis ; Mice ; Mice, Knockout ; Mitochondrial DNA ; Mutation ; Neurodegeneration ; Oncology ; Proteins ; R-loops ; Recombination ; Research and Analysis Methods ; Ribonucleic acid ; RNA ; RNA Helicases - genetics ; Rodents ; Spinocerebellar Ataxias - congenital ; Spinocerebellar Degenerations - genetics ; Transcription
    ISSN: 1932-6203
    E-ISSN: 1932-6203
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 3
    Language: English
    In: PloS one, 2016, Vol.11 (2), p.e0148213
    Description: Autosomal recessive ataxias are a clinically diverse group of syndromes that in some cases are caused by mutations in genes with roles in the DNA damage response, transcriptional regulation or mitochondrial function. One of these ataxias, known as Autosomal Recessive Cerebellar Ataxia Type-2 (ARCA-2, also known as SCAR9/COQ10D4; OMIM: #612016), arises due to mutations in the ADCK3 gene. The product of this gene (ADCK3) is an atypical kinase that is thought to play a regulatory role in coenzyme Q10 (CoQ10) biosynthesis. Although much work has been performed on the S. cerevisiae orthologue of ADCK3, the cellular and biochemical role of its mammalian counterpart, and why mutations in this gene lead to human disease is poorly understood. Here, we demonstrate that ADCK3 localises to mitochondrial cristae and is targeted to this organelle via the presence of an N-terminal localisation signal. Consistent with a role in CoQ10 biosynthesis, ADCK3 deficiency decreased cellular CoQ10 content. In addition, endogenous ADCK3 was found to associate in vitro with recombinant Coq3, Coq5, Coq7 and Coq9, components of the CoQ10 biosynthetic machinery. Furthermore, cell lines derived from ARCA-2 patients display signs of oxidative stress, defects in mitochondrial homeostasis and increases in lysosomal content. Together, these data shed light on the possible molecular role of ADCK3 and provide insight into the cellular pathways affected in ARCA-2 patients.
    Subject(s): Ataxia ; Autophagy ; Biology ; Biology and Life Sciences ; Biosynthesis ; Cell lines ; Cell Survival ; Cerebellar ataxia ; Cerebellum ; Coenzyme Q10 ; Cristae ; Cytosol - metabolism ; Defects ; Deoxyribonucleic acid ; DNA ; DNA Damage ; Endopeptidase K - metabolism ; Enzymes ; Gene expression ; Gene Expression Regulation ; Gene regulation ; Genes ; Genetic aspects ; Genetic transcription ; Glutathione Transferase - metabolism ; HeLa Cells ; Homeostasis ; Humans ; Ionizing radiation ; Kinases ; Lentivirus - genetics ; Lysosomes - metabolism ; Medical research ; Medicine and Health Sciences ; Membrane Potential, Mitochondrial ; Microscopy ; Mitochondria ; Mitochondria - metabolism ; Mitochondrial Proteins - genetics ; Mitochondrial Proteins - metabolism ; Mutagenesis, Site-Directed ; Mutation ; Oxidative Phosphorylation ; Oxidative Stress ; Patients ; Phosphorylation ; Protein Structure, Tertiary ; Proteins ; Reactive Oxygen Species - metabolism ; Recombinant Fusion Proteins - chemistry ; Research and analysis methods ; RNA Interference ; Saccharomyces cerevisiae - metabolism ; Saccharomyces cerevisiae Proteins - metabolism ; Transcription ; Ubiquinone - analogs & derivatives ; Ubiquinone - chemistry
    ISSN: 1932-6203
    E-ISSN: 1932-6203
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 4
    Language: English
    In: Nucleic acids research, 2020-02-20, Vol.48 (3), p.1271-1284
    Description: Abstract The healing of broken chromosomes by de novo telomere addition, while a normal developmental process in some organisms, has the potential to cause extensive loss of heterozygosity, genetic disease, or cell death. However, it is unclear how de novo telomere addition (dnTA) is regulated at DNA double-strand breaks (DSBs). Here, using a non-essential minichromosome in fission yeast, we identify roles for the HR factors Rqh1 helicase, in concert with Rad55, in suppressing dnTA at or near a DSB. We find the frequency of dnTA in rqh1Δ rad55Δ cells is reduced following loss of Exo1, Swi5 or Rad51. Strikingly, in the absence of the distal homologous chromosome arm dnTA is further increased, with nearly half of the breaks being healed in rqh1Δ rad55Δ or rqh1Δ exo1Δ cells. These findings provide new insights into the genetic context of highly efficient dnTA within HR intermediates, and how such events are normally suppressed to maintain genome stability.
    Subject(s): Chromosomes, Fungal - genetics ; DNA Breaks, Double-Stranded ; DNA Helicases - genetics ; DNA-Binding Proteins - genetics ; Exodeoxyribonucleases - genetics ; Gene Expression Regulation, Fungal - genetics ; Genome Integrity, Repair and ; Genome, Fungal - genetics ; Genomic Instability - genetics ; Loss of Heterozygosity - genetics ; Rad51 Recombinase - genetics ; Recombinational DNA Repair - genetics ; Schizosaccharomyces - genetics ; Schizosaccharomyces pombe Proteins - genetics ; Telomere - genetics
    ISSN: 0305-1048
    E-ISSN: 1362-4962
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 5
    Language: English
    In: Antibiotics (Basel), 2020-08-06, Vol.9 (8), p.487
    Description: Acronychia crassipetala is an endemic plant species in Australia. Its phytochemistry and therapeutic properties are underexplored. The hexane extract of the fruit A. crassipetala T. G. Hartley was found to inhibit the growth of the Gram-positive bacteria Staphylococcus aureus. Following bio-activity guided fractionation, two prenylated acetophenones, crassipetalonol A (1) and crassipetalone A (2), were isolated. Their structures were determined mainly by NMR and MS spectroscopic analyses. This is the first record of the isolation and structural characterisation of secondary metabolites from the species A. crassipetala. Their antibacterial and cytotoxic assessments indicated that the known compound (2) had more potent antibacterial activity than the antibiotic chloramphenicol, while the new compound (1) showed moderate cytotoxicity.
    Subject(s): Acronychia ; Acronychia crassipetala ; Antibacterial activity ; Antibiotics ; Bacteria ; Biological activity ; Cancer ; Chloramphenicol ; Chloromycetin ; Communication ; crassipetalone A ; crassipetalonol A ; Cytotoxicity ; Endemic plants ; Endemic species ; Fibroblasts ; Fractionation ; Gram-positive bacteria ; Health aspects ; Hydrocarbons ; Ketones ; Metabolites ; Native plants ; Natural products ; NMR ; Nuclear magnetic resonance ; Pathogens ; Plant species ; prenylated acetophenone ; Rainforests ; Secondary metabolites ; Toxicity
    ISSN: 2079-6382
    E-ISSN: 2079-6382
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
    Source: ProQuest Central
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  • 6
    Language: English
    In: PloS one, 2016, Vol.11 (7), p.e0160162-e0160162
    Description: [This corrects the article DOI: 10.1371/journal.pone.0148213.].
    Subject(s): Homeostasis ; Kinases ; Mitochondria ; Oxidative stress
    ISSN: 1932-6203
    E-ISSN: 1932-6203
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 7
    Language: English
    In: Investigational new drugs, 2018-04-18, Vol.37 (1), p.1-8
    Description: Summary The five-year survival rate for patients with head and neck squamous cell carcinoma (HNSCC) has remained at ~50% for the past 30 years despite advances in treatment. Tigilanol tiglate (TT, also known as EBC-46) is a novel diterpene ester that induces cell death in HNSCC in vitro and in mouse models, and has recently completed Phase I human clinical trials. The aim of this study was to optimise efficacy of TT treatment by altering different administration parameters. The tongue SCC cell line (SCC-15) was identified as the line with the lowest efficacy to treatment. Subcutaneous xenografts of SCC-15 cells were grown in BALB/c Foxn1 nu and NOD/SCID mice and treated with intratumoral injection of 30 μg TT or a vehicle only control (40% propylene glycol (PG)). Greater efficacy of TT treatment was found in the BALB/c Foxn1 nu mice compared to NOD/SCID mice. Immunohistochemical analysis indicated a potential role of the host’s innate immune system in this difference, specifically neutrophil infiltration. Neither fractionated doses of TT nor the use of a different excipiant led to significantly increased efficacy. This study confirmed that TT in 40% PG given intratumorally as a single bolus dose was the most efficacious treatment for a tongue SCC mouse model.
    Subject(s): Animal models ; Animals ; Antimitotic agents ; Antineoplastic agents ; Apoptosis ; Carcinoma, Squamous Cell - drug therapy ; Carcinoma, Squamous Cell - pathology ; Cell culture ; Cell death ; Cell Proliferation ; Cell survival ; Clinical trials ; Complications and side effects ; Diterpenes ; Diterpenes - pharmacology ; Dosage and administration ; Drug therapy ; Effectiveness ; Genetic aspects ; Head ; Head and neck cancer ; Humans ; Immune system ; Infiltration ; Innate immunity ; Life Sciences & Biomedicine ; Male ; Medical research ; Medicine ; Medicine & Public Health ; Mice ; Mice, Inbred BALB C ; Mice, Inbred NOD ; Mice, SCID ; Neutrophil Infiltration - drug effects ; Oncology ; Optimization ; Parameter identification ; Pharmacology & Pharmacy ; Pharmacology/Toxicology ; Preclinical Studies ; Propylene ; Propylene glycol ; Science & Technology ; Squamous cell carcinoma ; Studies ; Tongue ; Tongue Neoplasms - drug therapy ; Tongue Neoplasms - pathology ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays ; Xenografts ; Xenotransplantation
    ISSN: 0167-6997
    E-ISSN: 1573-0646
    Source: Web of Science - Science Citation Index Expanded - 2019〈img src="http://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /〉
    Source: Alma/SFX Local Collection
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  • 8
    Language: English
    In: Neuro-oncology (Charlottesville, Va.), 2020-02-20, Vol.22 (2), p.216-228
    Description: Abstract Background Despite significant endeavor having been applied to identify effective therapies to treat glioblastoma (GBM), survival outcomes remain intractable. The greatest nonsurgical benefit arises from radiotherapy, though tumors typically recur due to robust DNA repair. Patients could therefore benefit from therapies with the potential to prevent DNA repair and synergize with radiotherapy. In this work, we investigated the potential of salinomycin to enhance radiotherapy and further uncover novel dual functions of this ionophore to induce DNA damage and prevent repair. Methods In vitro primary GBM models and ex vivo GBM patient explants were used to determine the mechanism of action of salinomycin by immunoblot, flow cytometry, immunofluorescence, immunohistochemistry, and mass spectrometry. In vivo efficacy studies were performed using orthotopic GBM animal xenograft models. Salinomycin derivatives were synthesized to increase drug efficacy and explore structure-activity relationships. Results Here we report novel dual functions of salinomycin. Salinomycin induces toxic DNA lesions and prevents subsequent recovery by targeting homologous recombination (HR) repair. Salinomycin appears to target the more radioresistant GBM stem cell–like population and synergizes with radiotherapy to significantly delay tumor formation in vivo. We further developed salinomycin derivatives which display greater efficacy in vivo while retaining the same beneficial mechanisms of action. Conclusion Our findings highlight the potential of salinomycin to induce DNA lesions and inhibit HR to greatly enhance the effect of radiotherapy. Importantly, first-generation salinomycin derivatives display greater efficacy and may pave the way for clinical testing of these agents.
    Subject(s): Animals ; Autophagy - drug effects ; Basic and Translational Investigations ; Brain Neoplasms - pathology ; DNA damage ; DNA Replication - drug effects ; Drug Discovery ; glioblastoma ; Glioblastoma - pathology ; homologous recombination ; Humans ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Neoplastic Stem Cells - drug effects ; Neoplastic Stem Cells - pathology ; Pyrans - pharmacology ; Recombinational DNA Repair - drug effects ; Xenograft Model Antitumor Assays
    ISSN: 1522-8517
    E-ISSN: 1523-5866
    Source: PubMed Central
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  • 9
    Language: English
    In: The EMBO journal, 2009-11-04, Vol.28 (21), p.3400-3412
    Description: Loss of heterozygosity (LOH), a causal event in cancer and human genetic diseases, frequently encompasses multiple genetic loci and whole chromosome arms. However, the mechanisms by which such extensive LOH arises, and how it is suppressed in normal cells is poorly understood. We have developed a genetic system to investigate the mechanisms of DNA double‐strand break (DSB)‐induced extensive LOH, and its suppression, using a non‐essential minichromosome, Ch16, in fission yeast. We find extensive LOH to arise from a new break‐induced mechanism of isochromosome formation. Our data support a model in which Rqh1 and Exo1‐dependent end processing from an unrepaired DSB leads to removal of the broken chromosome arm and to break‐induced replication of the intact arm from the centromere, a considerable distance from the initial lesion. This process also promotes genome‐wide copy number variation. A genetic screen revealed Rhp51, Rhp55, Rhp57 and the MRN complex to suppress both isochromosome formation and chromosome loss, in accordance with these events resulting from extensive end processing associated with failed homologous recombination repair.
    Subject(s): Adenosine Triphosphatases - metabolism ; break-induced replication ; Centromere - genetics ; Chromosomes ; Chromosomes, Fungal - genetics ; Chromosomes, Fungal - metabolism ; copy number variation ; DNA Breaks, Double-Stranded ; DNA damage ; DNA-Binding Proteins - metabolism ; DSB ; Gene Conversion ; Genetic disorders ; homologous recombination ; isochromosome ; Loss of Heterozygosity ; Molecular biology ; Rad51 Recombinase - metabolism ; Schizosaccharomyces - genetics ; Schizosaccharomyces - metabolism ; Schizosaccharomyces pombe Proteins - metabolism ; Yeast
    ISSN: 0261-4189
    E-ISSN: 1460-2075
    Source: HighWire Press (Free Journals)
    Source: PubMed Central
    Source: Get It Now
    Source: Wiley-Blackwell Full Collection 2014
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  • 10
    Language: English
    In: Molecular and Cellular Biology, 2007-11-01, Vol.27 (21), p.7745-7757
    Description: Article Usage Stats Services MCB Citing Articles Google Scholar PubMed Related Content Social Bookmarking CiteULike Delicious Digg Facebook Google+ Mendeley Reddit StumbleUpon Twitter current issue Spotlights in the Current Issue MCB About MCB Subscribers Authors Reviewers Advertisers Inquiries from the Press Permissions & Commercial Reprints ASM Journals Public Access Policy MCB RSS Feeds 1752 N Street N.W. • Washington DC 20036 202.737.3600 • 202.942.9355 fax • journals@asmusa.org Print ISSN: 0270-7306 Online ISSN: 1098-5549 Copyright © 2014 by the American Society for Microbiology.   For an alternate route to MCB .asm.org, visit: MCB       
    Subject(s): Alleles ; Base Sequence ; Chromosomes, Fungal - metabolism ; Crossing Over, Genetic ; DNA Breaks, Double-Stranded ; DNA Repair ; Genetic Markers ; Loss of Heterozygosity - genetics ; Models, Genetic ; Molecular Sequence Data ; Multiprotein Complexes - metabolism ; Mutation - genetics ; Phylogeny ; Rad51 Recombinase - metabolism ; Recombination, Genetic ; Schizosaccharomyces - cytology ; Schizosaccharomyces - genetics ; Schizosaccharomyces pombe ; Schizosaccharomyces pombe Proteins - metabolism ; Telomere - metabolism ; Translocation, Genetic
    ISSN: 0270-7306
    E-ISSN: 1098-5549
    Source: HighWire Press (Free Journals)
    Source: Hellenic Academic Libraries Link
    Source: PubMed Central
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