Phospholipids and cholesterol: Inducers of cancer multidrug resistance and therapeutic targets.

Autor: Kopecka J; Department of Oncology, University of Torino, Italy., Trouillas P; UMR 1248 INSERM, Univeristy of Limoges, Limoges, France; RCPTM, University Palacký of Olomouc, Olomouc, Czech Republic., Gašparović AČ; Division of Molecular Medicine, Institute Ruđer Bošković, Zagreb, Croatia., Gazzano E; Department of Oncology, University of Torino, Italy., Assaraf YG; The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, Haifa, Israel., Riganti C; Department of Oncology, University of Torino, Italy; Interdepartmental Center of Research in Molecular Biotechnology, University of Torino, Italy. Electronic address: chiara.riganti@unito.it.
Jazyk: angličtina
Zdroj: Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy [Drug Resist Updat] 2020 Mar; Vol. 49, pp. 100670. Date of Electronic Publication: 2019 Nov 29.
DOI: 10.1016/j.drup.2019.100670
Abstrakt: Lipids, phospholipids and cholesterol in particular, are the predominant components of the plasma membrane, wherein multidrug efflux transporters of the ATP-binding cassette (ABC) superfamily reside as integral pump proteins. In the current review, we discuss how lipids potently modulate the expression and activity of these multidrug efflux pumps, contributing to the development of the multidrug resistance (MDR) phenotype in cancer. The molecular mechanisms underlying this modulation of the MDR phenotype are pleiotropic. First, notwithstanding the high intra-and inter-tumor variability, MDR cells display an altered composition of plasma membrane phospholipids and glycosphingolipids, and are enriched with very long saturated fatty acid chains. This feature, along with the increased levels of cholesterol, decrease membrane fluidity, alter the spatial organization of membrane nano- and micro-domains, interact with transmembrane helices of ABC transporters, hence favoring drug binding and release. Second, MDR cells exhibit a peculiar membrane lipid composition of intracellular organelles including mitochondria and endoplasmic reticulum (ER). In this respect, they contain a lower amount of oxidizable fatty acids, hence being more resistant to oxidative stress and chemotherapy-induced apoptosis. Third, drug resistant cancer cells have a higher ratio of monosatured/polyunsatured fatty acids: this lipid signature reduces the production of reactive aldehydes with cytotoxic and pro-inflammatory activity and, together with the increased activity of anti-oxidant enzymes, limits the cellular damage induced by lipid peroxidation. Finally, specific precursors of phospholipids and cholesterol including ceramides and isoprenoids, are highly produced in MDR cells; by acting as second messengers, they trigger multiple signaling cascades that induce the transcription of drug efflux transporter genes and/or promote a metabolic reprogramming which supports the MDR phenotype. High-throughput lipidomics and computational biology technologies are a great tool in analyzing the tumor lipid signature in a personalized manner and in identifying novel biomarkers of drug resistance. Moreover, beyond the induction of MDR, lipid metabolism offers a remarkable opportunity to reverse MDR by using lipid analogues and repurposing lipid-targeting drugs (e.g. statins and aminobisphosphonates) that reprogram the lipid composition of drug resistant cells, hence rendering them drug sensitive.
Competing Interests: Declaration of Competing Interest None.
(Copyright © 2019 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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