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IUBMB Life Dec 2017Synthetic lethality refers to a lethal phenotype that results from the simultaneous disruptions of two genes, while the disruption of either gene alone is viable. Many... (Review)
Review
Synthetic lethality refers to a lethal phenotype that results from the simultaneous disruptions of two genes, while the disruption of either gene alone is viable. Many DNA double strand break repair (DSBR) genes have synthetic lethal relationships with oncogenes and tumor suppressor genes, which can be exploited for targeted cancer therapy, an approach referred to as combination therapy. DNA double-strand breaks (DSBs) are one of the most toxic lesions to a cell and can be repaired by non-homologous end joining (NHEJ) or homologous recombination (HR). HR and NHEJ genes are particularly attractive targets for cancer therapy because these genes have altered expression patterns in cancer cells when compared with normal cells and these genetic abnormalities can be targeted for selectively killing cancer cells. Here, we review recent advances in the development of small molecule inhibitors against HR and NHEJ genes to induce synthetic lethality and address the future directions and clinical relevance of this approach. © 2017 IUBMB Life, 69(12):929-937, 2017.
Topics: Benzimidazoles; Cell Cycle; Chromones; Clinical Trials as Topic; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA, Neoplasm; Humans; Indoles; MRE11 Homologue Protein; Molecular Targeted Therapy; Morpholines; Neoplasms; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Pyrimidinones; Recombinational DNA Repair; Synthetic Lethal Mutations; Thiones
PubMed: 29171189
DOI: 10.1002/iub.1696 -
Molecules (Basel, Switzerland) Feb 2015We report here an efficient and green method for Biginelli condensation reaction of aldehydes, β-ketoesters and urea or thiourea catalyzed by Brønsted acidic ionic...
We report here an efficient and green method for Biginelli condensation reaction of aldehydes, β-ketoesters and urea or thiourea catalyzed by Brønsted acidic ionic liquid [Btto][p-TSA] under solvent-free conditions. Compared to the classical Biginelli reaction conditions, the present method has the advantages of giving good yields, short reaction times, near room temperature conditions and the avoidance of the use of organic solvents and metal catalyst.
Topics: Aldehydes; Catalysis; Ionic Liquids; Pyrimidinones; Solvents; Thiones; Thiourea
PubMed: 25730389
DOI: 10.3390/molecules20033811 -
Molecular Biology of the Cell Jun 2018The role of distinct actin filament architectures in epithelial plasticity remains incompletely understood. We therefore determined roles for formins and the Arp2/3...
The role of distinct actin filament architectures in epithelial plasticity remains incompletely understood. We therefore determined roles for formins and the Arp2/3 complex, which are actin nucleators generating unbranched and branched actin filaments, respectively, in the process of epithelial to mesenchymal transition (EMT). In clonal lung, mammary, and renal epithelial cells, the formin activity inhibitor SMIFH2 but not the Arp2/3 complex activity inhibitor CK666 blocked EMT induced by TGF-β. SMIFH2 prevented the proximal signal of increased Smad2 phosphorylation and hence also blocked downstream EMT markers, including actin filament remodeling, decreased expression of the adherens junction protein E-cadherin, and increased expression of the matrix protein fibronectin and the transcription factor Snail. The short hairpin RNA silencing of formins DIAPH1 and DIAPH3 but not other formins phenocopied SMIFH2 effects and inhibited Smad2 phosphorylation and changes in Snail and cadherin expression. Formin activity was not necessary for the cell surface expression or dimerization of TGF-β receptors, or for nuclear translocation of TAZ, a transcription cofactor in Hippo signaling also regulated by TGF-β. Our findings reveal a previously unrecognized role for formin-dependent actin architectures in proximal TGF-β signaling that is necessary for Smad2 phosphorylation but not for cross-talk to TAZ.
Topics: A549 Cells; Actin-Related Protein 2-3 Complex; Actomyosin; Adaptor Proteins, Signal Transducing; Animals; Cell Membrane; Epithelial-Mesenchymal Transition; Fetal Proteins; Formins; Humans; Mice; Microfilament Proteins; Nuclear Proteins; Phosphorylation; RNA, Small Interfering; Signal Transduction; Smad2 Protein; Thiones; Transforming Growth Factor beta; Uracil
PubMed: 29668357
DOI: 10.1091/mbc.E17-05-0325 -
Chemical & Pharmaceutical Bulletin 2021Cyclin dependent kinase 2 (CDK2) inhibition is a well-established strategy for treating cancer. Different series of novel thiazolone (1, 7-9) together with fused...
Cyclin dependent kinase 2 (CDK2) inhibition is a well-established strategy for treating cancer. Different series of novel thiazolone (1, 7-9) together with fused thiazolthione (2-6, and 10) derivatives were designed, then synthesized and evaluated for their biological inhibitory activity against CDK2. Additionally, the cytotoxicity of the new compounds was explored against breast and colon cancer cell lines. The novel thiazolone and the fused thiazolthione derivatives exhibited potent CDK2/cyclin A2 inhibitory effect of an IC values ranging 105.39-742.78 nM. Amongst them compounds 4 and 6 revealed highest IC of 105.39 and 139.27 nM, respectively. Most compounds showed significant inhibition on both breast cancer and colon cancer cell lines with IC range 0.54-5.26 and 0.83-278 µM, respectively. Further investigations involved flow cytometry analysis on MCF-7 cancer cell line for compounds 5 and 7 which resulted in arrest cell-cycle at two phases Pre G1/G2-M and re-enforced apoptosis via activation of caspase-7. Molecular modeling simulation of the designed compounds revealed that they were well fitted into CDK2 active site and their complexes were stabilized through the essential hydrogen bonding. Three dimensional quantitative structure activity relationship (3D QSAR) pharmacophore, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies were also carried out showing proper pharmacokinetic and drug-likeness which aided in the prediction of the structure requirements responsible for the observed antitumor activity.
Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase 2; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Protein Kinase Inhibitors; Quantitative Structure-Activity Relationship; Thiazoles; Thiones
PubMed: 33390512
DOI: 10.1248/cpb.c20-00714 -
International Journal of Biological... 2021Proliferation is one of the significant hallmarks of gallbladder cancer, which is a relatively rare but fatal malignance. Aim of this study was to examine the biological...
Proliferation is one of the significant hallmarks of gallbladder cancer, which is a relatively rare but fatal malignance. Aim of this study was to examine the biological impact and molecular mechanism of the candidate hub-gene on the proliferation and tumorigenesis of gallbladder cancer. We analyzed the differentially expressed genes and the correlation between these genes with MKI67, and showed that KIF11 is one of the major upregulated regulators of proliferation in gallbladder cancer (GBC). The Gene Ontology, Gene Sets Enrichment Analysis and KEGG Pathway analysis indicated that KIF11 may promote GBC cell proliferation through the ERBB2/PI3K/AKT signaling pathway. Gain-of-function and loss-of-function assay demonstrated that KIF11 regulated GBC cell cycle and cancer cell proliferation in vitro. GBC cells exhibited G2M phase cell cycle arrest, cell proliferation and clone formation ability reduction after treatment with Monastrol, a specific inhibitor of KIF11. Xenograft model showed that KIF11 promotes GBC growth in vivo. Rescue experiments showed that KIF11-induced GBC cell proliferation dependented on ERBB2/PI3K/AKT pathway. Moreover, we found that H3K27ac signals are enriched among the promoter region of KIF11 in the UCSC Genome Browser Database. Differentially expressed analysis showed that EP300, a major histone acetyltransferase modifying H3K27ac signal, is highly expressed in gallbladder cancer and correlation analysis illustrated that EP300 is positively related with KIF11 in almost all the cancer types. We further found that KIF11 was significantly downregulated in a dose-dependent and time-dependent manner after histone acetylation inhibitor treatment. The present results highlight that high KIF11 expression promotes GBC cell proliferation through the ERBB2/PI3K/AKT signaling pathway. The findings may help deepen our understanding of mechanism underlying GBC cancer development and development of novel diagnostic and therapeutic target.
Topics: Acetylation; Animals; Biomarkers, Tumor; Cell Cycle Checkpoints; Cell Proliferation; Female; Gallbladder Neoplasms; Heterografts; Histones; Humans; Kinesins; Mice; Mice, Nude; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Pyrimidines; Receptor, ErbB-2; Signal Transduction; Thiones
PubMed: 33613109
DOI: 10.7150/ijbs.54074 -
Environmental Health Perspectives Dec 1996A goal of our research is to identify biochemical factors that underlie the susceptibility of bone marrow cell populations to benzene metabolites so as to develop a... (Review)
Review
A goal of our research is to identify biochemical factors that underlie the susceptibility of bone marrow cell populations to benzene metabolites so as to develop a mechanistically based chemoprotective strategy that may be used in susceptible humans exposed to benzene. By doing biochemical risk analysis of bone marrow stromal cells from mice and rats and the human myeloid cell lines, HL-60 and ML-1; and by using buthionine sulfoximine and dicumarol we have observed that the susceptibility of these cell populations to hydroquinone (HQ) correlates with their concentration of glutathione (GSH) and activity of quinone reductase (QR). Accordingly, the induction of QR and GSH by 1,2-dithiole-3-thione (D3T) in these cell populations has resulted in a significant protection against the following hydroquinone-mediated toxicities: inhibition of cell proliferation and viability; reduced ability of stromal cells to support myelopoiesis; and altered differentiated of ML-1 cells to monocytes/macrophages. Preliminary in vivo experiments indicate that feeding mice D3T results in an induction of QR in the bone marrow compartment such that stromal cells are more resistant to hydroquinone-induced cytotoxicity in vitro. Overall, these studies suggest that in addition to hepatic cytochrome P4502E1, bone marrow QR and GSH are factors that could determine an individual's relative susceptibility to the toxic effects of benzene.
Topics: Animals; Benzene; Bone Marrow; Bone Marrow Cells; Cytochrome P-450 CYP2E1; Drug Resistance; Glutathione; Humans; Hydroquinones; Liver; Mice; NAD(P)H Dehydrogenase (Quinone); Rats; Thiones; Thiophenes
PubMed: 9118897
DOI: 10.1289/ehp.961041227 -
Biomolecules Feb 2022Mitochondria-targeted hydrogen sulfide (HS) donor compounds, such as compound AP39, supply HS into the mitochondrial environment and have shown several beneficial in...
Mitochondria-targeted hydrogen sulfide (HS) donor compounds, such as compound AP39, supply HS into the mitochondrial environment and have shown several beneficial in vitro and in vivo effects in cardiovascular conditions such as diabetes and hypertension. However, the study of their direct vascular effects has not been addressed to date. Thus, the objective of the present study was to analyze the effects and describe the mechanisms of action of AP39 on the in vitro vascular reactivity of mouse mesenteric artery. Protein and gene expressions of the HS-producing enzymes (CBS, CSE, and 3MPST) were respectively analyzed by Western blot and qualitative RT-PCR, as well the in vitro production of HS by mesenteric artery homogenates. Gene expression of CSE and 3MPST in the vessels has been evidenced by RT-PCR experiments, whereas the protein expression of all the three enzymes was demonstrated by Western blotting experiments. Nonselective inhibition of HS-producing enzymes by AOAA abolished HS production, whereas it was partially inhibited by PAG (a CSE selective inhibitor). Vasorelaxation promoted by AP39 and its HS-releasing moiety (ADT-OH) were significantly reduced after endothelium removal, specifically dependent on NO-cGMP signaling and SK channel opening. Endogenous HS seems to participate in the mechanism of action of AP39, and glibenclamide-induced K blockade did not affect the vasorelaxant response. Considering the results of the present study and the previously demonstrated antioxidant and bioenergetic effects of AP39, we conclude that mitochondria-targeted HS donors may offer a new promising perspective in cardiovascular disease therapeutics.
Topics: Animals; Mesenteric Arteries; Mice; Mitochondria; Thiones; Vasodilator Agents
PubMed: 35204781
DOI: 10.3390/biom12020280 -
PloS One 2018SHetA2 is a small molecule drug with promising cancer prevention and therapeutic activity and a high preclinical safety profile. The study objectives were to perform...
SHetA2 is a small molecule drug with promising cancer prevention and therapeutic activity and a high preclinical safety profile. The study objectives were to perform interspecies scaling and pharmacokinetic (PK) modeling of SHetA2 for human PK prediction. The PK data obtained from mice, rats, and dogs after intravenous and oral doses were used for simultaneous fitting to PK models. The disposition of SHetA2 was best described by a two-compartment model. The absorption kinetics was well characterized with a first-order absorption model for mice and rats, and a gastrointestinal transit model for dogs. Oral administration of SHetA2 showed a relatively fast absorption in mice, prolonged absorption (i.e., flip-flop kinetics) toward high doses in rats, and an early peak followed by a secondary peak at high doses in dogs. The oral bioavailability was 17.7-19.5% at 20-60 mg/kg doses in mice, <1.6% at 100-2000 mg/kg in rats, and 11.2% at 100 mg/kg decreasing to 3.45% at 400 mg/kg and 1.11% at 1500 mg/kg in dogs. The disposition parameters were well correlated with the body weight for all species using the allometric equation, which predicted values of CL (17.3 L/h), V1 (36.2 L), V2 (68.5 L) and CLD (15.2 L/h) for a 70-kg human. The oral absorption rate and bioavailability of SHetA2 was highly dependent on species, doses, formulations, and possibly other factors. The limited bioavailability at high doses was taken into consideration for the suggested first-in-human dose, which was much lower than the dose estimated based on toxicology studies. In summary, the present study provided the PK model for SHetA2 that depicted the disposition and absorption kinetics in preclinical species, and computational tools for human PK prediction.
Topics: Administration, Intravenous; Administration, Oral; Animals; Antineoplastic Agents; Biological Availability; Chromans; Dogs; Mice; Models, Biological; Rats; Species Specificity; Thiones
PubMed: 29634717
DOI: 10.1371/journal.pone.0194046 -
Molecular Cancer Therapeutics Nov 2008Dithiolethiones are a well-known class of cancer chemopreventive agents; the key mechanism of action of dithiolethiones involves activation of Nrf2 signaling and... (Review)
Review
Dithiolethiones are a well-known class of cancer chemopreventive agents; the key mechanism of action of dithiolethiones involves activation of Nrf2 signaling and induction of phase II enzymes. In the past, attention has been focused mainly on 4-methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione (oltipraz), which showed ability as a wide-spectrum inhibitor of chemical carcinogenesis in preclinical models. However, clinical trials of oltipraz have shown questionable efficacy, and at the high doses employed in such studies, significant side effects were observed. Dithiolethiones that are markedly more effective and potent than oltipraz in both induction of phase II enzymes and inhibition of chemical carcinogenesis in preclinical studies have been identified, and these compounds have shown pronounced organ specificity in vivo. Further investigation of these compounds may lead to development of effective and safe agents for cancer prevention in humans.
Topics: Animals; Anticarcinogenic Agents; Chemoprevention; Humans; Models, Biological; Neoplasms; Pyrazines; Thiones; Thiophenes
PubMed: 19001432
DOI: 10.1158/1535-7163.MCT-08-0625 -
Computational and Mathematical Methods... 2021Peripheral tissue damage leads to inflammatory pain, and inflammatory cytokine releasing is the key factor for inducing the sensitization of nociceptors. As a calcium...
Peripheral tissue damage leads to inflammatory pain, and inflammatory cytokine releasing is the key factor for inducing the sensitization of nociceptors. As a calcium ion channel, TRPA1 plays an important role in pain and inflammation, thus becoming a new type of anti-inflammatory and analgesic target. However, there is no consensus on the role of this channel in mechanical hyperalgesia caused by inflammation. Here, we aim to explore the role and underlying mechanism of the inflammasome inhibitor CY-09 in two classic inflammatory pain models. We evaluated pain behavior on animal models, cytokine levels, intracellular Ca levels, transient TRPA1 expression, NF-B transcription, and NLPR3 inflammasome activation. Consistently, CY-09 reduced the production of inflammatory cytokines, intracellular Ca levels, and the activation of TRPA1 by inhibiting the activation of inflammasomes, thereby reducing the proinflammatory polarization of macrophages and alleviating animal pain and injury. Importantly, AITC (TRPA1 agonist) significantly reversed the analgesic effect of CY-09, indicating that TRPA1 was involved in the analgesic effect of CY-09. Our findings indicate that CY-09 relieves inflammation and pain via inhibiting TRPA1-mediated activation of NLRP3 inflammasomes. Thus, NLRP3 inflammasome may be a potential therapeutic target for pain treatment and CY-09 may be a pharmacological agent to relieve inflammatory pain, which needs further research.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Calcium; Computational Biology; Cytokines; Disease Models, Animal; Inflammasomes; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Pain; Pain Measurement; TRPA1 Cation Channel; Thiazolidines; Thiones
PubMed: 34426748
DOI: 10.1155/2021/9806690