Drug Resistance in Cancer: An Overview

Cancers, Journal Year: 2014, Volume and Issue: 6(3), P. 1769 - 1792

Published: Sept. 5, 2014

Cancers have the ability to develop resistance traditional therapies, and increasing prevalence of these drug resistant cancers necessitates further research treatment development. This paper outlines current knowledge mechanisms that promote or enable resistance, such as inactivation, target alteration, efflux, DNA damage repair, cell death inhibition, epithelial-mesenchymal transition, well how inherent tumor heterogeneity plays a role in resistance. It also describes epigenetic modifications can induce considers factors may contribute development cancer progenitor cells, which are not killed by conventional therapies. Lastly, this review concludes with discussion on best options for existing cancers, ways prevent formation future directions study.

Language: Английский

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Arsenic and human health effects: A review

Environmental Toxicology and Pharmacology, Journal Year: 2015, Volume and Issue: 40(3), P. 828 - 846

Published: Oct. 3, 2015

Language: Английский

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EMT and tumor metastasis

Clinical and Translational Medicine, Journal Year: 2015, Volume and Issue: 4(1)

Published: Feb. 25, 2015

EMT and MET comprise the processes by which cells transit between epithelial mesenchymal states, they play integral roles in both normal development cancer metastasis. This article reviews these molecular pathways that contribute to them. First, we compare embryogenesis with We then discuss signaling differential expression down-regulation of receptors tumor stromal cells, a role further delve into clinical implications several types tumors, lastly, epigenetic events regulate EMT/MET processes. hypothesize reversible MET, thus, also different metastatic cancers.

Language: Английский

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Repurposing the CRISPR-Cas9 system for targeted DNA methylation

Nucleic Acids Research, Journal Year: 2016, Volume and Issue: 44(12), P. 5615 - 5628

Published: March 11, 2016

Epigenetic studies relied so far on correlations between epigenetic marks and gene expression pattern. Technologies developed for epigenome editing now enable direct study of functional relevance precise modifications regulation. The reversible nature modifications, including DNA methylation, has been already exploited in cancer therapy remodeling the aberrant landscape. However, this was achieved non-selectively using inhibitors. at specific loci represents a novel approach that might selectively heritably alter expression. Here, we CRISPR-Cas9-based tool methylation consisting deactivated Cas9 (dCas9) nuclease catalytic domain methyltransferase DNMT3A targeted by co–expression guide RNA to any 20 bp sequence followed NGG trinucleotide. We demonstrated CpG ∼35 wide region fusion protein. also showed multiple RNAs could target dCas9-DNMT3A construct adjacent sites, which enabled larger part promoter. activity heritable across mitotic divisions. Finally, directed wider promoter IL6ST BACH2 decreased their

Language: Английский

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In Vivo Target Gene Activation via CRISPR/Cas9-Mediated Trans-epigenetic Modulation

Cell, Journal Year: 2017, Volume and Issue: 171(7), P. 1495 - 1507.e15

Published: Dec. 1, 2017

Language: Английский

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Challenges and Opportunities in Cancer Drug Resistance

Chemical Reviews, Journal Year: 2020, Volume and Issue: 121(6), P. 3297 - 3351

Published: July 21, 2020

There has been huge progress in the discovery of targeted cancer therapies recent years. However, even for most successful and impactful drugs which have approved, both innate acquired mechanisms resistance are commonplace. These emerging studied intensively, enabled drug scientists to learn how it may be possible overcome such subsequent generations treatments. In some cases, novel candidates able supersede previously approved agents; other cases they used sequentially or combinations with existing This review summarizes current field terms challenges opportunities that presents scientists, a focus on small molecule therapeutics. As part this review, common themes approaches identified utilized successfully target resistance. includes increase potency selectivity, alternative chemical scaffolds, change mechanism action (covalents, PROTACs), increases blood-brain barrier permeability (BBBP), targeting allosteric pockets. Finally, wider covered as monoclonal antibodies (mAbs), bispecific antibodies, antibody conjugates (ADCs), combination therapies.

Language: Английский

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A cellular and molecular view of T helper 17 cell plasticity in autoimmunity

Journal of Autoimmunity, Journal Year: 2017, Volume and Issue: 87, P. 1 - 15

Published: Dec. 22, 2017

Since the original identification of T helper 17 (Th17) subset in 2005, it has become evident that these cells do not only contribute to host defence against pathogens, such as bacteria and fungi, but they are also critically involved pathogenesis many autoimmune diseases. In contrast classic Th1 Th2 cells, which represent rather stably polarized subsets, Th17 display remarkable heterogeneity plasticity. This been attributed characteristics key transcription factor guides differentiation, retinoic acid receptor-related orphan nuclear receptor gamma (RORγ). Unlike ‘master regulators’ T-bet GATA3 orchestrate respectively, RORγ controls at relatively few loci cells. Moreover, its expression is stabilized by positive feedback loops influenced environmental cues, allowing for substantial functional Importantly, a IL-17/IFNγ double-producing was identified both human mouse models. Evidence accumulating pathogenic drivers diseases, including rheumatoid arthritis, multiple sclerosis inflammatory bowel disease. addition, have disorders role autoimmunity remains unclear, sarcoidosis. The observed plasticity towards phenotype can be explained extensive epigenetic priming IFNG locus fact, an chromatin landscape remarkably similar On other hand, capabilities restrained stimulating IL-10 production transdifferentiation into producing regulatory type 1 (Tr1) this review, we discuss recent advances our knowledge on cellular molecular mechanisms We focus transcriptional regulation program, dynamics involved, how genetic variants associated with may affect immune responses through distal gene elements. Finally, implications cell treatment diseases will discussed.

Language: Английский

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New Targets for Schizophrenia Treatment beyond the Dopamine Hypothesis

International Journal of Molecular Sciences, Journal Year: 2017, Volume and Issue: 18(8), P. 1689 - 1689

Published: Aug. 3, 2017

Schizophrenia has been primarily associated with dopamine dysfunction, and treatments have developed that target the pathway in central nervous system. However, accumulating evidence shown core pathophysiology of schizophrenia might involve dysfunction dopaminergic, glutamatergic, serotonergic, gamma-aminobutyric acid (GABA) signaling, which may lead to aberrant functioning interneurons manifest as cognitive, behavioral, social through altered a broad range macro- microcircuits. The interactions between neurotransmitters can be modeled nodes edges by using graph theory, oxidative balance, immune, glutamatergic systems represent multiple interlocking at hub; imbalance within any these affect entire Therefore, this review attempts address novel treatment targets beyond hypothesis, including glutamate, serotonin, acetylcholine, GABA, inflammatory cytokines. Furthermore, we outline possibly integrated strategies aimed different symptoms or phases illness. We anticipate reversing anomalous activity combinations beneficial schizophrenia.

Language: Английский

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Epigenetics in male reproduction: effect of paternal diet on sperm quality and offspring health

Nature Reviews Urology, Journal Year: 2016, Volume and Issue: 13(10), P. 584 - 595

Published: Aug. 31, 2016

Language: Английский

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Targeted DNA methylation in vivo using an engineered dCas9-MQ1 fusion protein

Nature Communications, Journal Year: 2017, Volume and Issue: 8(1)

Published: July 11, 2017

Abstract Comprehensive studies have shown that DNA methylation plays vital roles in both loss of pluripotency and governance the transcriptome during embryogenesis subsequent developmental processes. Aberrant patterns been widely observed tumorigenesis, ageing neurodegenerative diseases, highlighting importance a systematic understanding dynamic changes methylomes disease onset progression. Here we describe facile convenient approach for efficient targeted by fusing inactive Cas9 (dCas9) with an engineered prokaryotic methyltransferase MQ1. Our study presents rapid strategy to achieve locus-specific cytosine modifications genome without obvious impact on global 24 h. Finally, demonstrate our tool can induce CpG mice zygote microinjection, thereby demonstrating its potential utility early development.

Language: Английский

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