scholarly journals Regulation of Cisplatin Cytotoxicity by Cu Influx Transporters

2010 ◽  
Vol 2010 ◽  
pp. 1-9 ◽  
Author(s):  
Paolo Abada ◽  
Stephen B. Howell
Keyword(s):  
Posttranscriptional Regulation ◽  
Drug Uptake ◽  
Common Mechanism ◽  
Platinum Drugs ◽  
Important Class ◽  
Cancer Chemotherapeutics ◽  
Development Of Resistance ◽  
Insight Into

Platinum drugs are an important class of cancer chemotherapeutics. However, the use of these drugs is limited by the development of resistance during treatment with decreased accumulation being a common mechanism. Both Cu transporters CTR1 and CTR2 influence the uptake and cytotoxicity of cisplatin. Although it is structurally similar to CTR1, CTR2 functions in a manner opposite to that of CTR1 with respect to Pt drug uptake. Whereas knockout of CTR1 reduces Pt drug uptake, knockdown of CTR2 enhances cisplatin uptake and cytotoxicity. CTR2 is subject to transcriptional and posttranscriptional regulation by both Cu and cisplatin; this regulation is partly dependent on the Cu chaperone ATOX1. Insight into the mechanisms by which CTR1 and CTR2 regulate sensitivity to the Pt-containing drugs has served as the basis for novel pharmacologic strategies for improving their efficacy.

A novel mechanism of Ha-ras oncogene action: regulation of fibronectin mRNA levels by a nuclear posttranscriptional event

1994 ◽  
Vol 14 (5) ◽  
pp. 3085-3093
Author(s):  
L A Chandler ◽  
C P Ehretsmann ◽  
S Bourgeois
Keyword(s):  
Posttranscriptional Regulation ◽  
Tail Length ◽  
Common Mechanism ◽  
Osteosarcoma Cell ◽  
Mrna Levels ◽  
Ras Oncogene ◽  
Down Regulation ◽  
Regulate Gene Expression ◽  
Protein Levels ◽  
Human Osteosarcoma Cell

Although loss of cell surface fibronectin (FN) is a hallmark of many oncogenically transformed cells, the mechanisms responsible for this phenomenon remain poorly understood. The present study utilized the nontumorigenic human osteosarcoma cell line TE-85 to investigate the effects of induced Ha-ras oncogene expression on FN biosynthesis. TE-85 cells were stably transfected with metallothionein-Ha-ras fusion genes, and the effects of metal-induced ras expression on FN biosynthesis were determined. Induction of the ras oncogene, but not proto-oncogene, was accompanied by a decrease in total FN mRNA and protein levels. Transfection experiments indicated that these oncogene effects were not due to reduced FN promoter activity, suggesting that a posttranscriptional mechanism was involved. The most common mechanism of posttranscriptional regulation affects cytoplasmic mRNA stability. However, in this study the down-regulation of FN was identified as a nuclear event. A component of the ras effect was due to a mechanism affecting accumulation of processed nuclear FN RNA. Mechanisms that would generate such an effect include altered RNA processing and altered stability of the processed message in the nucleus. There was no effect of ras on FN mRNA poly(A) tail length or site of polyadenylation. There was also no evidence for altered splicing at the ED-B domain of FN mRNA. This demonstration of nuclear posttranscriptional down-regulation of FN by the Ha-ras oncogene identifies a new level at which ras oncoproteins can regulate gene expression and thus contribute to development of the malignant phenotype.

scholarly journals KIF15 nanomechanics and kinesin inhibitors, with implications for cancer chemotherapeutics

2018 ◽  
Vol 115 (20) ◽  
pp. E4613-E4622 ◽  
Author(s):  
Bojan Milic ◽  
Anirban Chakraborty ◽  
Kyuho Han ◽  
Michael C. Bassik ◽  
Steven M. Block
Keyword(s):  
Cancer Cell ◽  
Small Molecule ◽  
Single Molecule ◽  
Small Molecule Inhibitors ◽  
Cancer Cell Growth ◽  
Combination Drug ◽  
Cancer Chemotherapeutics ◽  
Development Of Resistance ◽  
Molecule Inhibitor ◽  
Mechanochemical Cycle

Eg5, a mitotic kinesin, has been a target for anticancer drug development. Clinical trials of small-molecule inhibitors of Eg5 have been stymied by the development of resistance, attributable to mitotic rescue by a different endogenous kinesin, KIF15. Compared with Eg5, relatively little is known about the properties of the KIF15 motor. Here, we employed single-molecule optical-trapping techniques to define the KIF15 mechanochemical cycle. We also studied the inhibitory effects of KIF15-IN-1, an uncharacterized, commercially available, small-molecule inhibitor, on KIF15 motility. To explore the complementary behaviors of KIF15 and Eg5, we also scored the effects of small-molecule inhibitors on admixtures of both motors, using both a microtubule (MT)-gliding assay and an assay for cancer cell viability. We found that (i) KIF15 motility differs significantly from Eg5; (ii) KIF15-IN-1 is a potent inhibitor of KIF15 motility; (iii) MT gliding powered by KIF15 and Eg5 only ceases when both motors are inhibited; and (iv) pairing KIF15-IN-1 with Eg5 inhibitors synergistically reduces cancer cell growth. Taken together, our results lend support to the notion that a combination drug therapy employing both inhibitors may be a viable strategy for overcoming chemotherapeutic resistance.

Parallel RNAi and compound screens identify the PDK1 pathway as a target for tamoxifen sensitization

2008 ◽  
Vol 417 (1) ◽  
pp. 361-371 ◽  
Author(s):  
Elizabeth Iorns ◽  
Christopher J. Lord ◽  
Alan Ashworth
Keyword(s):  
Breast Cancer ◽  
Oestrogen Receptor ◽  
Kinase Inhibitors ◽  
Genetic Screen ◽  
Genetic Screens ◽  
Development Of Resistance ◽  
Chemical Screen ◽  
Related Proteins ◽  
Insight Into ◽  
Treat Breast Cancer

Tamoxifen is the most commonly used drug to treat breast cancer and acts by blocking ERα (oestrogen receptor α) signalling. Although highly effective, its usefulness is limited by the development of resistance. Given this, strategies that limit resistance by sensitizing cells to tamoxifen may be of use in the clinic. To gain insight into how this might be achieved, we used chemical and genetic screens to identify targets and small-molecule inhibitors that cause tamoxifen sensitization. A high-throughput genetic screen, using an RNA interference library targeting 779 kinases and related proteins, identified the PDK1 (phosphoinositide-dependent kinase 1) signalling pathway as a strong determinant of sensitivity to multiple ERα antagonists, including tamoxifen. A chemical screen using existing drugs and known kinase inhibitors also identified inhibitors of the PDK1 pathway, including triciribine and tetrandrine. Aside from identifying novel agents and targets for tamoxifen sensitization, this approach also provides evidence that performing chemical and genetic screens in parallel may be useful.

Operando Monitoring of Charging Processes in Battery Cathodes by Magnetometry and Positron Annihilation

2021 ◽  
Vol 1016 ◽  
pp. 1647-1652
Author(s):  
Gregor Klinser ◽  
Heinz Krenn ◽  
Roland Würschum
Keyword(s):  
Positron Annihilation ◽  
Positron Lifetime ◽  
Transition Metal Ions ◽  
Important Class ◽  
Vanadium Phosphate ◽  
Battery Charging ◽  
Battery Materials ◽  
Oxide Cathode ◽  
Highly Sensitive ◽  
Insight Into

Research in the field of modern battery materials demands characterization techniques which allow an inspection of atomistic processes during battery charging and discharging. Two powerful tools for this purpose are magnetometry and positron-electron annihilation. The magnetic moment serves as highly sensitive fingerprint for the oxidation state of the transition metal ions, thus enabling to identify the electrochemical ”active” ions. The positron lifetime on the other hand, is sensitive to open volume defects of the size of a few missing atoms down to single vacancies providing an unique insight into lattice defects induced by charging and discharging. An overview will be given on operando magnetometry studies of the important class of LiNiCoMn-oxide cathode materials (so-called NMC with Ni:Co:Mn ratios of 1:1:1 and 3:1:1) as well as of sodium vanadium phosphate cathodes. First operando positron annihilation studies on a battery cathode material (NMC 1:1:1) demonstrate the capability of this technique for battery research.

scholarly journals Trichlorination of a Teicoplanin-Type Glycopeptide Antibiotic by the Halogenase StaI Evades Resistance

2018 ◽  
Vol 62 (12) ◽  
Author(s):  
Grace Yim ◽  
Wenliang Wang ◽  
Andrew C. Pawlowski ◽  
Gerard D. Wright
Keyword(s):  
Biological Function ◽  
Antibiotic Activity ◽  
Important Class ◽  
Glycopeptide Antibiotics ◽  
Glycopeptide Antibiotic ◽  
Content Type ◽  
Specialized Metabolites ◽  
Chemically Modified ◽  
Induction Of Resistance ◽  
Insight Into

ABSTRACT Glycopeptide antibiotics (GPAs) include clinically important drugs used for the treatment of infections caused by Gram-positive pathogens. These antibiotics are specialized metabolites produced by several genera of actinomycete bacteria. While many GPAs are highly chemically modified, A47934 is a relatively unadorned GPA lacking sugar or acyl modifications, common to other members of the class, but which is chlorinated at three distinct sites. The biosynthesis of A47934 is encoded by a 68-kb gene cluster in Streptomyces toyocaensis NRRL 15009. The cluster includes all necessary genes for the synthesis of A47934, including two predicted halogenase genes, staI and staK. In this study, we report that only one of the halogenase genes, staI, is necessary and essential for A47934 biosynthesis. Chlorination of the A47934 scaffold is important for antibiotic activity, as assessed by binding affinity for the target N-acyl-d-Ala-d-Ala. Surprisingly, chlorination is also vital to avoid activation of enterococcal and Streptomyces VanB-type GPA resistance through induction of resistance genes. Phenotypic assays showed stronger induction of GPA resistance by the dechlorinated compared to the chlorinated GPA. Correspondingly, the relative expression of the enterococcal vanA resistance gene was shown to be increased by the dechlorinated compared to the chlorinated compound. These results provide insight into the biosynthesis of GPAs and the biological function of GPA chlorination for this medically important class of antibiotic.

Prospective Evaluation of MRD-Kinetics in 274 Children with High-Risk ALL Treated in Trial ALL-BFM 2000: Insights into Development of Resistance and Impact on Further Refinement of Treatment Stratification Strategies.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 585-585 ◽  
Author(s):  
André Schrauder ◽  
Martin Stanulla ◽  
Thomas Flohr ◽  
Gunnar Cario ◽  
Rolf Köhler ◽  
...  
Keyword(s):  
High Risk ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Initial Response ◽  
Induction Treatment ◽  
Event Free Survival ◽  
Free Survival ◽  
Development Of Resistance ◽  
Consolidation Phase ◽  
Insight Into

Abstract In trial ALL-BFM 2000, high-risk (HR) acute lymphoblastic leukemia (ALL) is defined by inadequate initial response to induction treatment [poor prednisone response on treatment day eight, non remission on treatment day 33, and/or a high load of minimal residual disease (MRD, ≥10E-3) after 12 weeks of treatment (TP2)] and/or by cytogenetics [t(4;11 or t(9;22)]. Between August 1999 and November 2006, 494 (15%) out of 3255 study patients were stratified into the HR branch of trial ALL-BFM 2000. 431 (87%) of these HR patients underwent successful MRD monitoring at TP2 with 274 (56%) patients having received additional extensive prospective MRD monitoring subsequent to TP2. Patients with an indication for stem cell transplantation (SCT) and a suitable donor were scheduled for SCT within six weeks after the third HR block of the intensive consolidation phase. The estimated 4-years event-free-survival (4y-pEFS) for the entire HR group was 68%+/−3%, estimated survival was 74%+/−3%. Patients with MRD load of ≤10E-4 at TP2 (n=231) had a 4y-pEFS of 82%+/−3%, patients with MRD levels of 10E-3 at TP2 (n=84) had a 4y-pEFS of 74%+/−6%, and patients with MRD of >10E-3 at TP2 (n=116) had a 4y-pEFS of 35%+/−5%. MRD-kinetics subsequent to TP2 revealed, that 85% of all patients with an MRD level of 10E-3 at TP2 continued to decrease their load below 10E-3 during the pulsatile intensive consolidation phase, whereas this was observed in only 35% of patients with an MRD level of >10E-3 at TP2. The 4y-pEFS of patients with an MRD load persisting at 10E-2 after application of three intensive HR blocks after TP2 was 0% if no SCT was performed, and 33%+/−11% after SCT in CR1. Our data reflect that extensive MRD measurements in HR-ALL patients allow a dynamic insight into the development of resistance, and serve as valuable tool for further clinical treatment adjustment. “MRD non-response” after three BFM HR blocks identifies a patient group in urgent need of alternative treatment elements, closely monitored by MRD, before going into SCT in CR1.

scholarly journals Cisplatin and beyond: molecular mechanisms of action and drug resistance development in cancer chemotherapy

2019 ◽  
Vol 53 (2) ◽  
pp. 148-158 ◽  
Author(s):  
Tomaz Makovec
Keyword(s):  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Large Body ◽  
Chemical Properties ◽  
Platinum Complexes ◽  
Platinum Drugs ◽  
Metal Compounds ◽  
Development Of Resistance ◽  
Covalent Adducts

AbstractBackgroundPlatinum-based anticancer drugs are widely used in the chemotherapy of human neoplasms. The major obstacle for the clinical use of this class of drugs is the development of resistance and toxicity. It is therefore very important to understand the chemical properties, transport and metabolic pathways and mechanism of actions of these compounds. There is a large body of evidence that therapeutic and toxic effects of platinum drugs on cells are not only a consequence of covalent adducts formation between platinum complexes and DNA but also with RNA and many proteins. These processes determine molecular mechanisms that underlie resistance to platinum drugs as well as their toxicity. Increased expression levels of various transporters and increased repair of platinum-DNA adducts are both considered as the most significant processes in the development of drug resistance. Functional genomics has an increasing role in predicting patients’ responses to platinum drugs. Genetic polymorphisms affecting these processes may play an important role and constitute the basis for individualized approach to cancer therapy. Similar processes may also influence therapeutic potential of nonplatinum metal compounds with anticancer activity.ConclusionsCisplatin is the most frequently used platinum based chemotherapeutic agent that is clinically proven to combat different types of cancers and sarcomas.

II. Contribution towards the history of thialdine

1857 ◽  
Vol 8 ◽  
pp. 491-494
Keyword(s):  
Important Class ◽  
Organic Bases ◽  
History Of ◽  
Insight Into

Researches into the behaviour of several organic bases with bi-sulphide of carbon, which I intend to lay before the Society at a later period, have led to some experiments with thialdine, the results of which I may be allowed briefly to state, since they are but loosely connected with the principal object of the inquiry. It appeared of interest to gain some insight into the constitution of thialdine, which is the prototype of an important class of alkaloids containing sulphur.

scholarly journals Quantitative profiling of protease specificity

2020 ◽  
Author(s):  
B. I. Ratnikov ◽  
P. Cieplak ◽  
A. G. Remacle ◽  
E. Nguyen ◽  
J. W. Smith
Keyword(s):  
Substrate Recognition ◽  
Quantitative Measure ◽  
Detailed Knowledge ◽  
Important Class ◽  
Protease Specificity ◽  
Pathologic Processes ◽  
Catalytic Cleft ◽  
Insight Into ◽  
Generation Sequencing ◽  
Quantitative Profiling

AbstractProteases comprise an important class of enzymes, whose activity is central to many physiologic and pathologic processes. Detailed knowledge of protease specificity is key to understanding their function. Although many methodologies have been developed to profile specificities of proteases, few have the diversity and quantitative grasp necessary to fully define specificity of a protease, both in terms of substrate numbers and their catalytic efficiencies. We have developed a concept of “selectome”, which defines the set of substrates that uniquely represents specificity of a protease. We applied it to two closely related members of the Matrixin family – MMP-2 and MMP-9 by using substrate phage display coupled with Next Generation Sequencing and information theory-based data analysis. We have also derived a quantitative measure of substrate specificity, which accounts for both the numbers and relative catalytic efficiencies of substrates. Using these advances greatly facilitates uncovering selectivity between closely related members of protease families and provides insight into to the degree of contribution of catalytic cleft specificity to protein substrate recognition, thus providing basis to overcoming two of the major challenges in the field of proteolysis: 1) development of highly selective activity probes and inhibitors for studying proteases with overlapping specificities, and 2) distinguishing targeted proteolysis from bystander proteolytic events.

scholarly journals Targeting HER 1 and 2 in breast cancer with lapatinib

2011 ◽  
pp. 21-28
Author(s):  
Gerald M. Higa
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Kinase Inhibitor ◽  
Therapeutic Option ◽  
Family Members ◽  
Disease Relapse ◽  
Her Family ◽  
Development Of Resistance ◽  
Improved Outcomes ◽  
Insight Into

Numerous clinical trials support the biological relevance of the HER2 oncoprotein in breast cancer. In spite of improved outcomes, overexpression of the receptor is associated with increased risks of disease relapse, even in patients with early, and potentially curable, disease. Until recently, development of resistance to trastuzumab left patients with no therapeutic option other than specifically targeted HER2. This paper provides an in-depth review of lapatinib, a dual HER kinase inhibitor, as well as some insight into three HER family members, in breast cancer.

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