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[PMID]: 29517131
[Au] Autor:Chen B; Gianolio DA; Stefano JE; Manning CM; Gregory RC; Busch MM; Brondyk WH; Miller RJ; Dhal PK
[Ad] Address:Sanofi Global R&D, 153 Second Avenue, Waltham, MA, 02139, USA.
[Ti] Title:Design, Synthesis, and in vitro Evaluation of Multivalent Drug Linkers for High-Drug-Load Antibody-Drug Conjugates.
[So] Source:ChemMedChem;, 2018 Mar 08.
[Is] ISSN:1860-7187
[Cp] Country of publication:Germany
[La] Language:eng
[Ab] Abstract:A series of novel multivalent drug linkers (MDLs) containing cytotoxic agents were synthesized and conjugated to antibodies to yield highly potent antibody-drug conjugates (ADCs) with drug/antibody ratios (DARs) higher than those typically reported in the literature (10 vs. ≈4). These MDLs contain two copies of a cytotoxic agent attached to biocompatible scaffolds composed of a branched peptide core and discrete polyethylene glycol (PEG) chains to enhance solubility and decrease aggregation. These drug linkers produced well-defined ADCs, whose DARs could be accurately determined by LC-MS. Using this approach, ADCs with significantly lower aggregation and higher DAR than those of conventional drug linker design were obtained with highly hydrophobic cytotoxic agents such as monomethyldolastatin 10 (MMAD). The in vitro potencies of the MDL-derived conjugates matched that of ADCs of similar DAR with conventional linkers, and the potency increased proportionally with drug loading. This approach may provide a means to prepare highly potent ADCs from a broader range of drugs, including those with lower cytotoxicity or poor solubility, which otherwise limits their use for antibody-drug conjugates. This may also provide a means to further improve the potency achievable with cytotoxins currently used in ADCs.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180308
[Lr] Last revision date:180308
[St] Status:Publisher
[do] DOI:10.1002/cmdc.201700722

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[PMID]: 29216958
[Au] Autor:Guesmi F; Ben Hadj AS; Landoulsi A
[Ad] Address:Laboratory of Biochemistry and Molecular Biology, Faculty of Sciences of Bizerte, University of Carthage, Zarzouna 7021, Tunisia.
[Ti] Title:Investigation of Extracts from Tunisian Ethnomedicinal Plants as Antioxidants, Cytotoxins, and Antimicrobials.
[So] Source:Biomed Environ Sci;30(11):811-824, 2017 Nov.
[Is] ISSN:0895-3988
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:OBJECTIVE: To determine the medicinal potential of various plants and their parts extracted with different solvents. METHODS: The total phenolic content of acetonitrile/water (60%-40%) (ACN/W) and aqueous (W) extract fractions was determined by high-performance liquid chromatography (HPLC), and terpenic compounds were detected by gas chromatography/mass spectrometry (GC/MS). Antioxidant activity of the samples was evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay and -carotene bleaching method. Cell viability was investigated by thiazolyl blue tetrazolium bromide [3-(4,5-dimethylthiazol)-2-yl 2,5-diphenyltetrazolium bromide] (MTT) assay. The mechanisms involved in cytotoxic activity were investigated in a murine macrophage cell line (RAW 264.7) and cancer lines. RESULTS: Our findings show that 11 plant species exhibited biological activity. In addition, moderate antibacterial activity was reported against one or more of the tested bacterial strains at two concentrations: 300 g and 3 mg/disc. Furthermore, our data reveal that among all plants investigated, some extract and hydrophobic fractions were potent scavengers of the DPPH radical (6.78 g/mL < EC50 < 8.55 g/mL). Taken together, our results show that Nerium oleander (NOACN/W) and Pituranthos tortuosus (PTACN/W) were highly cytotoxic against RAW 264.7 cells with IC80 values of 0.36, and 1.55 g/mL, respectively. In contrast, murine macrophage cell lines had low growth and were significantly sensitive to water extracts of Thymus hirtus sp. algeriensis (THW), Lavandula multifida (LMW), and ACN/W extract of Erica multiflora (EMACN/W) at doses > 400, 47.20, and 116.74 g/mL, respectively. The current work demonstrates that RAW 264.7 cell proliferation was inhibited by samples in a dose-dependent manner. CONCLUSION: Our findings, validated through free radical scavenging activity, agar diffusion assay, and cytotoxicity of essential oils towards cancer cells, show that ethnomedicinal plants used in this work have a novel application as a tumor suppressor.
[Mh] MeSH terms primary: Anti-Bacterial Agents/pharmacology
Antineoplastic Agents, Phytogenic/pharmacology
Cytotoxins/pharmacology
Plant Extracts/pharmacology
Plants, Medicinal/chemistry
[Mh] MeSH terms secundary: Animals
Anti-Bacterial Agents/chemistry
Antineoplastic Agents, Phytogenic/chemistry
Bacteria/drug effects
Biphenyl Compounds
Cell Line
Cytotoxins/chemistry
Ethnobotany
Mice
Molecular Structure
Phenols/chemistry
Phenols/pharmacology
Picrates
Plant Extracts/chemistry
Terpenes/chemistry
Terpenes/pharmacology
Tunisia
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Anti-Bacterial Agents); 0 (Antineoplastic Agents, Phytogenic); 0 (Biphenyl Compounds); 0 (Cytotoxins); 0 (Phenols); 0 (Picrates); 0 (Plant Extracts); 0 (Terpenes); DFD3H4VGDH (1,1-diphenyl-2-picrylhydrazyl)
[Em] Entry month:1803
[Cu] Class update date: 180305
[Lr] Last revision date:180305
[Js] Journal subset:IM
[Da] Date of entry for processing:171209
[St] Status:MEDLINE
[do] DOI:10.3967/bes2017.109

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[PMID]: 29461834
[Au] Autor:Shen X; Laber CH; Sarkar U; Galazzi F; Johnson KM; Mahieu NG; Hillebrand R; Fuchs-Knotts T; Barnes CL; Baker GA; Gates KS
[Ad] Address:Department of Chemistry, Department of Biochemistry, and Molecular Interaction Core, University of Missouri 125 Chemistry Building Columbia, Missouri 65211, United States.
[Ti] Title:Exploiting the Inherent Photophysical Properties of the Major Tirapazamine Metabolite in the Development of Profluorescent Substrates for Enzymes That Catalyze the Bioreductive Activation of Hypoxia-Selective Anticancer Prodrugs.
[So] Source:J Org Chem;, 2018 Feb 26.
[Is] ISSN:1520-6904
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Hypoxia-selective cytotoxins (HSCs) seek to exploit the oxygen-poor nature of tumor tissue for therapeutic gain. Typically, HSCs require activation by one-electron bioreductive enzymes such as NADPH:cytochrome P450 reductase (CYPOR). Thus, successful clinical deployment of HSCs may be facilitated by the development and implementation of diagnostic probes that detect the presence of relevant bioreductive enzymes in tumor tissue. The work described here develops analogues of the well-studied HSC tirapazamine (3-amino-1,2,4-benzotriazine 1,4-di-N-oxide, TPZ) as profluorescent substrates of the one-electron reductases involved in bioactivation of HSCs. Hypoxic metabolism of TPZ or 7-fluoro-TPZ by one-electron reductases releases inherently fluorescent mono-N-oxide metabolites that may serve as indicators, probes, markers, or stains for the detection of the enzymes involved in the bioactivation of HSCs. In particular, profluorescent compounds of this type can provide a foundation for fluorescence-based bioassays that help identify tumors responsive to HSCs.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180226
[Lr] Last revision date:180226
[St] Status:Publisher
[do] DOI:10.1021/acs.joc.7b03035

  4 / 8203 MEDLINE  
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[PMID]: 29254300
[Au] Autor:Khalid M; Bilal M; Hassani D; Iqbal HMN; Huang D
[Ad] Address:School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, China.
[Ti] Title:Antimicrobial, antioxidant, cytotoxicity and LC-MS analyses of Aerva javanica: an ethnomedicinally important plant.
[So] Source:J Biol Regul Homeost Agents;31(4):963-969, 2017 Oct-Dec.
[Is] ISSN:0393-974X
[Cp] Country of publication:Italy
[La] Language:eng
[Ab] Abstract:In this study, Aerva javanica was used to extract the essential oil with notable medicinal activities. The chemical composition was investigated by high-performance liquid chromatography (HPLC) and liquid chromatography/mass spectrometry (LC-MS). Ten major chemical compounds were identified as flavonoids derivatives, dihydroxylated and glycosylated metabolites. The antimicrobial, antioxidant, and cytotoxicity activities were tested using agar well-diffusion assay, 1, 1-diphenyl-2-picrylhydrazyl (DPPH) free-radical scavenging and linoleic acid oxidation assays and hemolytic assay against human erythrocytes (RBCs), respectively. Plant extracts exhibited different extents of antimicrobial activities against selected bacterial and fungal strains; however, the essential oil displayed potent antimicrobial activity against all the tested strains. The percentage inhibition of linoleic acid oxidation and inhibitory concentration (IC50) were recorded to be in the range of 42.45-96.21% and 14.21-38.18 g/mL, respectively. Cytotoxicity profile of A. javanica extracts and essential oil was found in the range of 5.82 to 14.47%. In conclusion, A. javanica essential oil could be a potential alternative to chemical additives in the food and pharmaceutical industries.
[Mh] MeSH terms primary: Amaranthaceae/chemistry
Anti-Infective Agents/pharmacology
Antioxidants/pharmacology
Cytotoxins/pharmacology
Flavonoids/pharmacology
Oils, Volatile/pharmacology
[Mh] MeSH terms secundary: Anti-Infective Agents/isolation & purification
Antioxidants/isolation & purification
Biphenyl Compounds/antagonists & inhibitors
Biphenyl Compounds/chemistry
Cytotoxins/isolation & purification
Flavonoids/isolation & purification
Fungi/drug effects
Fungi/growth & development
Gram-Negative Bacteria/drug effects
Gram-Negative Bacteria/growth & development
Gram-Positive Bacteria/drug effects
Gram-Positive Bacteria/growth & development
Inhibitory Concentration 50
Linoleic Acid/chemistry
Microbial Sensitivity Tests
Oils, Volatile/isolation & purification
Oxidation-Reduction
Picrates/antagonists & inhibitors
Picrates/chemistry
Plant Extracts/chemistry
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Anti-Infective Agents); 0 (Antioxidants); 0 (Biphenyl Compounds); 0 (Cytotoxins); 0 (Flavonoids); 0 (Oils, Volatile); 0 (Picrates); 0 (Plant Extracts); 9KJL21T0QJ (Linoleic Acid); DFD3H4VGDH (1,1-diphenyl-2-picrylhydrazyl)
[Em] Entry month:1802
[Cu] Class update date: 180222
[Lr] Last revision date:180222
[Js] Journal subset:IM
[Da] Date of entry for processing:171220
[St] Status:MEDLINE

  5 / 8203 MEDLINE  
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[PMID]: 28452946
[Au] Autor:Li Y; Zhao Y; Zhou X; Ni W; Dai Z; Yang D; Hao J; Luo L; Liu Y; Luo X; Zhao X
[Ad] Address:Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, 21 Qingsong Road, Kunming 650203, China. liyuan@mail.kiz.ac.cn.
[Ti] Title:Cytotoxic Indole Alkaloid 3α-Acetonyltabersonine Induces Glioblastoma Apoptosis via Inhibition of DNA Damage Repair.
[So] Source:Toxins (Basel);9(5), 2017 Apr 28.
[Is] ISSN:2072-6651
[Cp] Country of publication:Switzerland
[La] Language:eng
[Ab] Abstract:Cytotoxic indole alkaloids from , which belongs to the toxic plant family Apocynaceae, demonstrated impressive antitumor activities in many tumor types, but less application in glioblastoma, which is the lethal brain tumor. In the present study, we reported the anti-glioblastoma activity of an indole alkaloid, 3 -acetonyltabersonine, which was isolated from . 3 -acetonyltabersonine was cytotoxic to glioblastoma cell lines (U87 and T98G) and stem cells at low concentrations. We verified 3 -acetonyltabersonine could suppress tumor cell proliferation and cause apoptosis in glioblastoma stem cells (GSCs). Moreover, detailed investigation of transcriptome study and Western blotting analysis indicated the mitogen activated protein kinase (MAPK) pathway was activated by phosphorylation upon 3 -acetonyltabersonine treatment. Additionally, we found 3 -acetonyltabersonine inhibited DNA damage repair procedures, the accumulated DNA damage stimulated activation of MAPK pathway and, finally, induced apoptosis. Further evidence was consistently obtained from vivo experiments on glioblastoma mouse model: treatment of 3 -acetonyltabersonine could exert pro-apoptotic function and prolong the life span of tumor-bearing mice. These results in vitro and in vivo suggested that 3 -acetonyltabersonine could be a potential candidate antitumor agent.
[Mh] MeSH terms primary: Antineoplastic Agents/pharmacology
Cytotoxins/pharmacology
Glioblastoma/genetics
Indole Alkaloids/pharmacology
[Mh] MeSH terms secundary: Animals
Antineoplastic Agents/therapeutic use
Apoptosis/drug effects
Cell Line, Tumor
Cell Proliferation/drug effects
DNA Damage
DNA Repair/drug effects
Glioblastoma/drug therapy
Humans
Indole Alkaloids/therapeutic use
Male
Mice, Inbred C57BL
Mitogen-Activated Protein Kinases/metabolism
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Antineoplastic Agents); 0 (Cytotoxins); 0 (Indole Alkaloids); EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
[Em] Entry month:1802
[Cu] Class update date: 180222
[Lr] Last revision date:180222
[Js] Journal subset:IM
[Da] Date of entry for processing:170429
[St] Status:MEDLINE

  6 / 8203 MEDLINE  
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[PMID]: 29464939
[Au] Autor:Tchagang CF; Xu R; Doumbou CL; Tambong JT
[Ad] Address:Ottawa Research and Development Centre, Ottawa, ON, Canada.
[Ti] Title:Genome analysis of two novel Pseudomonas strains exhibiting differential hypersensitivity reactions on tobacco seedlings reveals differences in nonflagellar T3SS organization and predicted effector proteins.
[So] Source:Microbiologyopen;, 2018 Feb 21.
[Is] ISSN:2045-8827
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Multilocus sequence analysis (MLSA) of two new biological control strains (S1E40 and S3E12) of Pseudomonas was performed to assess their taxonomic position relative to close lineages, and comparative genomics employed to investigate whether these strains differ in key genetic features involved in hypersensitivity responses (HRs). Strain S3E12, at high concentration, incites HRs on tobacco and corn plantlets while S1E40 does not. Phylogenies based on individual genes and 16S rRNA-gyrB-rpoB-rpoD concatenated sequence data show strains S1E40 and S3E12 clustering in distinct groups. Strain S3E12 consistently clustered with Pseudomonas marginalis, a bacterium causing soft rots on plant tissues. MLSA data suggest that strains S1E40 and S3E12 are novel genotypes. This is consistent with the data of genome-based DNA-DNA homology values that are below the proposed cutoff species boundary. Comparative genomics analysis of the two strains revealed major differences in the type III secretion systems (T3SS) as well as the predicted T3SS secreted effector proteins (T3Es). One nonflagellar (NF-T3SS) and two flagellar T3SSs (F-T3SS) clusters were identified in both strains. While F-T3SS clusters in both strains were relatively conserved, the NF-T3SS clusters differed in the number of core components present. The predicted T3Es also differed in the type and number of CDSs with both strains having unique predicted protease-related effectors. In addition, the T1SS organization of the S3E12 genome has protein-coding sequences (CDSs) encoding for key factors such as T1SS secreted agglutinin repeats-toxins (a group of cytolysins and cytotoxins), a membrane fusion protein (LapC), a T1SS ATPase of LssB family (LapB), and T1SS-associated transglutaminase-like cysteine proteinase (LapP). In contrast, strain S1E40 has all CDSs for the seven-gene operon (pelA-pelG) required for Pel biosynthesis but not S3E12, suggesting that biofilm formation in these strains is modulated differently. The data presented here provide an insight of the genome organization of these two phytobacterial strains.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180221
[Lr] Last revision date:180221
[St] Status:Publisher
[do] DOI:10.1002/mbo3.553

  7 / 8203 MEDLINE  
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[PMID]: 28457141
[Au] Autor:Liu X; Zhang P; Rdl W; Maier K; Lchelt U; Wagner E
[Ad] Address:Pharmaceutical Biotechnology, Center for System-based Drug Research and Center for NanoScience (CeNS), Ludwig-Maximilians-Universitt Mnchen , Butenandtstrasse 5-13, D-81377 Munich, Germany.
[Ti] Title:Toward Artificial Immunotoxins: Traceless Reversible Conjugation of RNase A with Receptor Targeting and Endosomal Escape Domains.
[So] Source:Mol Pharm;14(5):1439-1449, 2017 May 01.
[Is] ISSN:1543-8392
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:The specific transport of bioactive proteins into designated target cells is an interesting and challenging perspective for the generation of innovative biopharmaceuticals. Natural protein cytotoxins perform this task with outstanding efficacy. They enter cells with receptor-targeted specificity, respond to changing intracellular microenvironments, and by various mechanisms translocate their cytotoxic protein subunit into the cytosol. Here we imitate this toxin-based delivery strategy in an artificial setting, by bioreversible conjugation of a cytotoxic cargo protein (RNase A) with receptor-targeting PEG-folate and the pH-specific endosomolytic peptide INF7 as synthetic delivery domains. Covalent modification of the cargo protein was achieved using the pH-labile AzMMMan linker and copper-free click chemistry with DBCO-modified delivery modules. This linkage is supposed to enable traceless intracellular release of the RNase A after exposure to the endosomal weakly acidic environment. Delivery of RNase A via this polycation-free delivery strategy resulted in high cytotoxicity against receptor-positive KB tumor cells only when both PEG-folate and INF7 were attached.
[Mh] MeSH terms primary: Click Chemistry/methods
Endosomes/metabolism
Immunotoxins/chemistry
Ribonuclease, Pancreatic/chemistry
[Mh] MeSH terms secundary: Cell Line, Tumor
Electrophoresis, Polyacrylamide Gel
Folic Acid/analogs & derivatives
Folic Acid/chemistry
Humans
Hydrogen-Ion Concentration
Immunotoxins/metabolism
Models, Biological
Peptides/chemistry
Polyethylene Glycols/chemistry
Ribonuclease, Pancreatic/metabolism
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (INF7 peptide); 0 (Immunotoxins); 0 (Peptides); 0 (poly(ethylene glycol)-folate); 30IQX730WE (Polyethylene Glycols); 935E97BOY8 (Folic Acid); EC 3.1.27.5 (Ribonuclease, Pancreatic)
[Em] Entry month:1802
[Cu] Class update date: 180220
[Lr] Last revision date:180220
[Js] Journal subset:IM
[Da] Date of entry for processing:170502
[St] Status:MEDLINE
[do] DOI:10.1021/acs.molpharmaceut.6b00701

  8 / 8203 MEDLINE  
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[PMID]: 28470525
[Au] Autor:Brown JP; Lynch BS; Curry-Chisolm IM; Shafer TJ; Strickland JD
[Ad] Address:Integrated Systems Toxicology Division, NHEERL, US EPA, MD105-05, Research Triangle Park, NC, 27711, USA.
[Ti] Title:Assaying Spontaneous Network Activity and Cellular Viability Using Multi-well Microelectrode Arrays.
[So] Source:Methods Mol Biol;1601:153-170, 2017.
[Is] ISSN:1940-6029
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Microelectrode array (MEA) technology is a neurophysiological method that allows for the spontaneous measure of activity in neural cultures and determination of drug and chemical effects thereon. Recent introduction of multi-well MEA (mwMEA) formats have dramatically increased the throughput of this technology, allowing more efficient compound screening. Rapid characterization of compounds for neuroactivity or neurotoxicity hazard evaluation following acute, chronic, or developmental exposures ideally would also consider compound effects on cell health, and to do so in the same well requires a multiplexed approach. Procedures describing the multiplexed method to acute and developmental screening are described in this chapter.
[Mh] MeSH terms primary: Cell Survival/drug effects
Cytotoxins/toxicity
Microarray Analysis/instrumentation
Microelectrodes
Nerve Net/drug effects
Neurons/drug effects
Toxicity Tests/instrumentation
[Mh] MeSH terms secundary: Animals
Neocortex/cytology
Primary Cell Culture
Rats
Rats, Long-Evans
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Cytotoxins)
[Em] Entry month:1802
[Cu] Class update date: 180219
[Lr] Last revision date:180219
[Js] Journal subset:IM
[Da] Date of entry for processing:170505
[St] Status:MEDLINE
[do] DOI:10.1007/978-1-4939-6960-9_13

  9 / 8203 MEDLINE  
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[PMID]: 29457584
[Au] Autor:Schora DM; Peterson LR; Usacheva EA
[Ad] Address:1Infectious Disease Research,NorthShore University HealthSystem,Evanston,Illinois.
[Ti] Title:Immunological Stability of Clostridium difficile Toxins in Clinical Specimens.
[So] Source:Infect Control Hosp Epidemiol;:1-5, 2018 Feb 19.
[Is] ISSN:1559-6834
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:OBJECTIVE The impact of storage on stability and detection of Clostridium difficile toxins in feces is poorly understood. The objective of this study was to investigate the immunological stability of C. difficile toxins in clinical stool specimens under different storage conditions by evaluating this stability using toxin detection by enzyme immunoassay (EIA). METHODS Stool specimens positive for C. difficile infection (CDI) by quantitative polymerase chain reaction (qPCR) were used for EIA testing with the C. difficile Tox A/B II kit. The EIA-positive specimens were stored aerobically under refrigerated (4-10C) and frozen (-30C and -80C) conditions. Measurement of toxin quantity was conducting using optical density (OD) on days 0, 14, 30, 60, 90, and 120 of storage. RESULTS Clostridium difficile toxins demonstrated good detection in undiluted stool specimens by EIA up to 120 days of storage. Good detection of the toxins was observed in diluted samples at refrigerated and -80C temperatures. Dilution detrimentally affected toxin detection at -30C. CONCLUSION Storage of undiluted clinical stool specimens at refrigerated, -30C, and -80C temperatures for up to 120 days has no discernible effect on the immunological stability of C. difficile cytotoxins. However, storage at -30C has a detrimental effect on C. difficile toxin stability in diluted specimens. Infect Control Hosp Epidemiol 2018;1-5.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180219
[Lr] Last revision date:180219
[St] Status:Publisher
[do] DOI:10.1017/ice.2018.20

  10 / 8203 MEDLINE  
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[PMID]: 29426932
[Au] Autor:Beztsinna N; de Matos MBC; Walther J; Heyder C; Hildebrandt E; Leneweit G; Mastrobattista E; Kok RJ
[Ad] Address:Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
[Ti] Title:Quantitative analysis of receptor-mediated uptake and pro-apoptotic activity of mistletoe lectin-1 by high content imaging.
[So] Source:Sci Rep;8(1):2768, 2018 Feb 09.
[Is] ISSN:2045-2322
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Ribosome inactivating proteins (RIPs) are highly potent cytotoxins that have potential as anticancer therapeutics. Mistletoe lectin 1 (ML1) is a heterodimeric cytotoxic protein isolated from European Mistletoe and belongs to RIP class II. The aim of this project was to systematically study ML1 cell binding, endocytosis pathway(s), subcellular processing and apoptosis activation. For this purpose, state of the art cell imaging equipment and automated image analysis algorithms were used. ML1 displayed very fast binding to sugar residues on the membrane and energy-dependent uptake in CT26 cells. The co-staining with specific antibodies and uptake blocking experiments revealed involvement of both clathrin-dependent and -independent pathways in ML1 endocytosis. Co-localization studies demonstrated the toxin transport from early endocytic vesicles to Golgi network; a retrograde road to the endoplasmic reticulum. The pro-apoptotic and antiproliferative activity of ML1 were shown in time lapse movies and subsequently quantified. ML1 cytotoxicity was less affected in multidrug resistant tumor cell line 4T1 in contrast to commonly used chemotherapeutic drug (ML1 resistance index 6.9 vs 13.4 for doxorubicin; IC : ML1 1.4 ng/ml vs doxorubicin 24000 ng/ml). This opens new opportunities for the use of ML1 as an alternative treatment in multidrug resistant cancers.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180216
[Lr] Last revision date:180216
[St] Status:In-Data-Review
[do] DOI:10.1038/s41598-018-20915-y


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