Book ChapterDOI
Mechanisms of multidrug resistance in cancer.
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TLDR
Identifying genes and mechanisms critical to the development of MDR in vivo and establishing a reliable method for analyzing clinical samples could help to predict theDevelopment of resistance and lead to treatments designed to circumvent it.Abstract:
The development of multidrug resistance (MDR) to chemotherapy remains a major challenge in the treatment of cancer. Resistance exists against every effective anticancer drug and can develop by numerous mechanisms including decreased drug uptake, increased drug efflux, activation of detoxifying systems, activation of DNA repair mechanisms, evasion of drug-induced apoptosis, etc. In the first part of this chapter, we briefly summarize the current knowledge on individual cellular mechanisms responsible for MDR, with a special emphasis on ATP-binding cassette transporters, perhaps the main theme of this textbook. Although extensive work has been done to characterize MDR mechanisms in vitro, the translation of this knowledge to the clinic has not been crowned with success. Therefore, identifying genes and mechanisms critical to the development of MDR in vivo and establishing a reliable method for analyzing clinical samples could help to predict the development of resistance and lead to treatments designed to circumvent it. Our thoughts about translational research needed to achieve significant progress in the understanding of this complex phenomenon are therefore discussed in a third section. The pleotropic response of cancer cells to chemotherapy is summarized in a concluding diagram.read more
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Journal ArticleDOI
Monitoring Drug Target Engagement in Cells and Tissues Using the Cellular Thermal Shift Assay
Daniel Martinez Molina,Rozbeh Jafari,Marina Ignatushchenko,Takahiro Seki,E. Andreas Larsson,Chen Dan,Lekshmy Sreekumar,Yihai Cao,Yihai Cao,Pär Nordlund,Pär Nordlund +10 more
TL;DR: This cellular thermal shift assay (CETSA) is based on the biophysical principle of ligand-induced thermal stabilization of target proteins and validated drug binding for a set of important clinical targets and monitored processes of drug transport and activation, off-target effects and drug resistance in cancer cell lines, as well as drug distribution in tissues.
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Cisplatin Resistance: A Cellular Self-Defense Mechanism Resulting from Multiple Epigenetic and Genetic Changes
TL;DR: Decreased accumulation is one of the most common features resulting in cisplatin resistance, and seems to be a consequence of numerous epigenetic and genetic changes leading to the loss of cell-surface binding sites and/or transporters for cisPlatin, and decreased fluid phase endocytosis.
Journal ArticleDOI
Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade.
Zhaolin Chen,Tianlu Shi,Lei Zhang,Pengli Zhu,Mingying Deng,Cheng Huang,Tingting Hu,Ling Jiang,Jun Li +8 more
TL;DR: Recent findings suggest that efflux pumps of the ABC transporter family are subject to epigenetic gene regulation, and this review summarizes recent findings of the role of ABC efflux transporters in MDR.
Journal ArticleDOI
The modulation of ABC transporter-mediated multidrug resistance in cancer: a review of the past decade.
TL;DR: The development of new compounds and the re-evaluation of compounds originally designed for other targets as transport inhibitors of ATP-dependent drug efflux pumps are summarized.
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The Clinical Relevance of Cancer Cell Lines
TL;DR: This work reviews the major events in the development of the in vitro models and the emergence of new technologies that have revealed important issues and limitations concerning human cancer cell lines as models and develops new in vitro preclinical models that would substantially increase the success rate ofnew in vitro-assessed cancer treatments.
References
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Reduced endocytosis and altered lysosome function in cisplatin-resistant cell lines
S S Chauhan,Xing-Jie Liang,A W Su,A Pai-Panandiker,D W Shen,J A Hanover,Michael M. Gottesman +6 more
TL;DR: Results indicate inefficient degradation of internalised 125I-EGF in the lysosomes of KB-CP-r cells, consistent with slower processing of cathepsin L, a lysOSomal cysteine protease, and defective endosomal acidification may contribute to acquired cisplatin resistance.
Journal ArticleDOI
Up-regulation of vaults may be necessary but not sufficient for multidrug resistance.
Amara C. Siva,Sujna Raval-Fernandes,Andrew G. Stephen,Michael J. LaFemina,R. J. Scheper,Valerie A. Kickhoefer,Leonard H. Rome +6 more
TL;DR: It is demonstrated that while vault levels may be a good predictor of drug resistance, their up‐regulation alone is not sufficient to confer the drug‐resistant phenotype, which implies a requirement of an additional factor(s) for vault‐mediated MDR.
Journal ArticleDOI
ABC proteins: key molecules for lipid homeostasis.
TL;DR: The general structure and functions of eukaryotic ABC proteins are described and the current model of ABCA1 functionality is explained based on studies on a topological model, subcellular localization, apoA-I dependence of HDL formation, functional defects of Tangier disease mutants, and ATP hydrolysis of purifiedABCA1.
Journal ArticleDOI
Characterisation of high-level cisplatin-resistant cell lines established from a human hepatoma cell line and human KB adenocarcinoma cells: cross-resistance and protein changes.
TL;DR: Results suggest that alterations of certain proteins occur commonly in cisplatin-resistant cells, particularly proteins of molecular weight 52 and 50 kDa, which are known substrates for the multidrug transporter.
Journal ArticleDOI
RLIP76 and Cancer
Sanjay Awasthi,Sharad S. Singhal,Yogesh C. Awasthi,Bryan Martin,Jung Hee Woo,Casey Cunningham,Arthur E. Frankel +6 more
TL;DR: RLIP76 is a multifunctional membrane protein that transports glutathione conjugates of electrophilic compounds and other xenobiotics including chemotherapy agents out of cells and is found throughout the cell, in membrane, cytosol, and the nucleus and is known to shift between these compartments in response to stress.