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.
Journal ArticleDOI
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
Substrate recognition and transport by multidrug resistance protein 1 (ABCC1)
Roger G. Deeley,Susan P.C. Cole +1 more
TL;DR: Current knowledge of the substrate specificity and modes of transport of MRP1 are summarized and how the protein may recognize its structurally diverse substrates are discussed.
Journal ArticleDOI
ATR Kinase Activation Mediated by MutSα and MutLα in Response to Cytotoxic O6-Methylguanine Adducts
TL;DR: It is shown that checkpoint signaling in response to DNA methylation occurs during S phase and requires DNA replication that gives rise to O 6 -meG/T mispairs, and suggested that MMR proteins can act as direct sensors of methylation damage and help recruit ATR-ATRIP to sites of cytotoxic O 6-meG adducts to initiate ATR checkpoint signaling.
Journal ArticleDOI
Membrane Transporters and Channels: Role of the Transportome in Cancer Chemosensitivity and Chemoresistance
Ying Huang,Pascale Anderle,Kimberly J. Bussey,Catalin Barbacioru,Uma Shankavaram,Zunyan Dai,William C. Reinhold,Audrey C. Papp,John N. Weinstein,Wolfgang Sadee +9 more
TL;DR: Several potential drug-transporter relationships are identified and a prominent role for membrane transport in determining chemosensitivity is supported, supported by measurement of transporter gene expression, which may prove useful in predicting anticancer drug response.
Journal ArticleDOI
ATP binding cassette transporters and drug resistance in breast cancer.
F Leonessa,Robert Clarke +1 more
TL;DR: In vitro studies on primary cultures of breast cancer cells obtained at surgery consistently show an association between Pgp (protein) or MDR1 (mRNA) expression and resistance to chemotherapy, however, the correlation with clinical drug resistance is not as well defined.
Journal ArticleDOI
Characterization of Drug Transport by the Human Multidrug Resistance Protein 3 (ABCC3)
TL;DR: The resistance to etoposide was associated with reduced cellular accumulation and enhanced efflux of this drug and was not affected by depleting cells of glutathione but was inhibited by several common organic anion transport inhibitors.