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.
Journal ArticleDOI
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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Journal ArticleDOI
Investigation of MRP-1 protein and MDR-1 P-glycoprotein expression in invasive breast cancer: a prognostic study.
Annemarie Larkin,Lorraine O'Driscoll,Susan Kennedy,Susan Kennedy,Rachel V. Purcell,Rachel V. Purcell,Elizabeth Moran,John Crown,Michael Parkinson,Martin Clynes +9 more
TL;DR: Assessment of MRP‐1 expression at diagnosis may offer useful prognostic information in subgroups of patients with stage 1 or stage 2 high‐grade tumours who receive CMF‐based adjuvant chemotherapy.
Journal ArticleDOI
Ceramide and glucosylceramide upregulate expression of the multidrug resistance gene MDR1 in cancer cells.
Valérie Gouazé-Andersson,Jing Y. Yu,Adam J. Kreitenberg,Alicja Bielawska,Armando E. Giuliano,Myles C. Cabot +5 more
TL;DR: It is shown that high levels of ceramide and GC enhance expression of the multidrug resistance phenotype in cancer cells, and ceramide's role as a messenger of cytotoxic response might be linked to the multodrug resistance pathway.
Journal ArticleDOI
Overexpression of lung‐resistance protein and increased P‐glycoprotein function in acute myeloid leukaemia cells predict a poor response to chemotherapy and reduced patient survival
TL;DR: Both LRP and Pgp are clinically relevant drug‐resistance proteins and it may be necessary to modulate both L RP and P gp functions in order to reverse the multidrug resistance phenotype in AML.
Journal ArticleDOI
Mining and visualizing large anticancer drug discovery databases.
Leming M. Shi,Yi Fan,Jae K. Lee,Mark Waltham,Darren T. Andrews,Uwe Scherf,Kenneth D. Paull,John N. Weinstein +7 more
TL;DR: Mining the database of screened compounds in vitro for the development of anticancer drugs, for a better understanding of the molecular pharmacology of cancer, and for improvement of the drug discovery process can provide useful information.
Journal ArticleDOI
Role of alterations in the apoptotic machinery in sensitivity of cancer cells to treatment.
TL;DR: Current knowledge concerning function of apoptotic machinery in cancer cells is reviewed, and how this information can be used to increase the efficiency of tumor treatment is reviewed.