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In Resistance to Adriamycin and Taxol by the K562 Leukemia Cell Line

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In Resistance to Adriamycin and Taxol by the K562 Leukemia Cell Line [CANCER RESEARCH56. 3461-3467, August 1, 19961 Proton Nuclear Magnetic Resonance Spectroscopy Reveals Cellular Lipids Involved in Resistance to Adriamycin and Taxol by the K562 Leukemia Cell Line Laurence Le Moyec,' Roger Tatoud, Armelle Degeorges, Cynthia Calabresse, Guy Bauza, Michel Eugene, and Fabien Calvo Laboratoire ik RMN et Exploration Fonctionnelle IL L M., G. B., M. E.] and Laboratoire de Pharmacologie Expérimentale [R. T., A. D., F. C.], Hôpital Saint Louis. 27 rue Juliette Dodu, and Laboratoire de Biologic Cellulaire Hématopolétique.Institut Universitaire d'Hématologie, I avenue Claude Vellefaux (C. C.]. 75010 Paris, France ABSTRACT modification of the plasma membrane structure (1). In the case of Taxol, which normally inhibits microtubule disaggregation, abnormal Proton nuclear magnetic resonance spectroscopy was performed on tubulin requiring Taxol to polymerize has been evidenced (4) in whole cells to study lipids and metabolites in Adriamycin- and Taxol Taxol-resistant cells. resistant K562 cells expressing multidrug resistance (MDR) and their sensitive counterparts. With one-dimensional spectra, both resistant cell The plasma membrane plays a key role in the control of intracel lines showed lower fatty acid methylene:methyl ratios and higher choline: lular concentration, and its lipid composition may alter drug efflux methyl ratios than sensitive cells. Using two-dimensional COSY spectra, a and influx. Membrane lipid composition of sensitive and resistant decrease In the glutamine content was evidenced in resistant cells. When tumor cells has been studied, in particular, with anthracycline antibi these cells were maintained in culture mediwn without the drug, the fatty otics (Adriamycin and daunorubicin). These DNA-targeting drugs acid signals were partially recovered. Adriamycm-resistant K562 cells also have membrane effects and, when linked to polymers carriers, were also treated for 4 days with a high dose of verapamil, a MDR can be active without entering cells. They bind electrostatically to reversing agent. The nuclear magnetic resonance spectra of vernpamil membrane lipids and to negatively charged phospholipids via weaker treated cells also showed partial recovery of fatty acid signals. These hydrophobic interactions. Adriamycin interacts with membranes by results could be paralleled with the reversion of the resistant phenotype, as evidenced by measuring the inhibiting concentration of Adriamycin increasing the turnover of phosphatidylinositol (5). Thus, modifica and vinblastine in K562adr cells cultured without the drug or after tions in membrane composition have consequences on cell surface short-term exposure to verapamil. Conversely, P-glycoprotein and mRNA charges and on membrane fluidity, altering drug binding and drug expression and DNA amplification of the mdr gene were not modified uptake. The nature of these lipid modifications has been studied in when compared to resistant cells, suggesting that the MDR phenotype several works, but a general lipid profile for resistant cells has not yet could be partially reversed independently of the mdr gene amplification come forth. For example, P388 daunorubicin-resistant cells bind less and expression. These results demonstrate the role of lipids in the resist drug than their sensitive counterparts (6). This result was related to a ance phenomenon. lower phosphatidylserine content and a higher cholesterol content in drug-resistant cells. In human leukemic lymphoblasts, the develop INTRODUCTION ment of vinblastine resistance was associated with an increase in ether lipids, cholesterol, and phospholipids (7). Another way to investigate The term MDR2 phenomenon describes cellular expression of the relationship between lipids and resistance is to modify the lipid resistance to drugs without necessarily related origin or chemical membrane composition. In human ovarian cancer cells, Adriamycin similarities (for review, see Refs. 1—3).TheMDR is related to a lower resistance can be increased by lowering the membrane cholesterol intracellular concentration of drugs. The most widely evoked and content when cells are cultured in medium without lipoproteins, and studied mechanism is the presence, in the membrane of MDR cells, of this effect is reversed by vp (8). Polyunsaturated fatty acids were a P-gp (or gp-170), working as an AlP-dependent pump to increase shown to decrease the vincristine resistance of human neuroblastoma the drug efflux. This P-gp is encoded by a family of mdr genes cells by changing the phospholipid membrane composition (9) and overexpressed in resistant cell lines. that of human cervical carcinoma (10) by increasing membrane flu However, other mechanisms are also responsible for the decrease in idity, which was also related to increased sensitivity of resistant drug accumulation. Drug uptake may be reduced, intracellular degra Ll2lO cells (1 1). The mechanism may not simply be a matter of drug dation of drugs may be increased, and metabolism into active corn diffusion since the use of known membrane fluidizers decreases drug pounds may be altered (1). Besides, drug effects may be altered by uptake by P-gp in rat liver canalicular membrane vesicles (12). In modification of cellular targets (enzyme, protein, or DNA) and by Ehrlich ascites tumor cells, the level of resistance was reported to be improvement of DNA repair. These mechanisms may coexist with dependent on the level ofphospholipids of the plasma membrane (13). P-gp and with each other, depending on the type of drug used to Proton NMR spectroscopy is able to detect the mobile fraction of induce resistance. In the case of Adriamycin resistance, several mech lipids contained in the cell, and thus is sensitive to membrane fluidity anisms were described: increased enzyme activities such as that of the modifications related to lipid composition changes (14—16).Since the enzyme responsible for detoxification by glutathione, decreased ac chemical analysis of membrane lipids reflects the quantity of different tivity of the nuclear enzyme topoisomerase II, decreased transforma lipids, NMR spectroscopy can provide an assessment of the physical tion of the drug into semiquinone, which can react with oxygen to state of these lipids and detect changes in membrane fluidity in form active oxygen radicals, and reduced intracellular diffusion by relation to drug resistance. With this aim, we studied the human leukemia K562 cell line using Received 3/4/96; accepted 5/28/96. The costs of publication of this article were defrayed in part by the payment of page proton NMR spectroscopy and compared it to Adriamycin- (K562adr) charges. This article must therefore be hereby marked advertisement in accordance with and Taxol- (K562tax) resistant cell lines, both overexpressing the mdr 18 U.S.C. Section 1734 solely to indicate this fact. gene. Because the lipids detected using NMR were affected in resist I To whom requests for reprints should be addressed. @ 2 abbreviations used are: MDR, multidrug resistance; P-gp, P-glycoprotein; NMR, ant cells, we altered resistance by maintaining the cells in medium nuclear magnetic resonance; Glu, glutamine-glutamate; Ct, creatine-creatinine; Chol, without the drug and measured the consequences on NMR spectra. On choline and derivative compounds; lao, inositol; Eth, ethanolamine; vp. verapamil; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IC,0, 10% inhibitory concentra K562adr, the consequences of resistance reversion using this method tion. and short-term exposure to high doses of vp were investigated with 3461 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1996 American Association for Cancer Research. PROTON NMR OF MDR K562 CELLS proton spectroscopy, measurement of drug sensitivity, and expression denaturing gel containing 2% formaldehyde. RNAs were transferred to an of the mdr gene (mRNA, P-gp, and DNA). Amersham Hybond C membrane. Hybridization was performed at 42°Cfor 12 h in buffer containing 50% (v/v) formamide, lx Denhardt's solution, 5X SSC,2.5 mMsodiumphosphate,0.25mg/mIsingle-strandherringspermDNA, MATERIALS AND METHODS and 10% dextran sulfate, with the random priming 32P-labeled probe (Multi prime DNA labeling system; Arnersham). After removing unbound probe, the Cell Culture. The K562wtcell line is a humanleukemiacell line (17). The filters were exposed at —80°ConKodak X-OMAT AR film with intensifying Adriamycin-resistant derived cell line K562adr was a gift from Dr. T. Tsuruo screens. (Japanese Foundation for Cancer Research, Tokyo, Japan) and the Taxol Probes used were: mdrl, 600 bp of pCHP1 genomic fragment (provided by resistant derived cell line K562tax was a gift from C. Tempéte(Institut de Dr. V. Ling, Ontario Cancer Institute, Toronto, Ontario, Canada); p53, 1.3-kb Chimie des Substances Naturelles, Gif sur Yvette, France). PvuH cDNA fragment from the p53-H-8 clone (20); and GAPDH, 1.2-kb Pst! K562 cells were cultured in RPMI 1640 (Sigma, St. Quentin Fallavier, fragment from rat GAPDH (21). France) supplemented with 10% FCS (ATGC, Noisy le Grand, France) and 4 Cytofluorimetry. The monoclonal antibody MRK16 is a murine IgG2a mM glutamine (Sigma). The resistant cells were cultured in the same medium developed and kindly offered by Dr. H. Hamada and Dr. T. Tsuruo (22). This containing 0.5 ,.@g/mlAdriamycin(Farmitalia Carlo Erba, Rueil Malmaison, antibody reacts with an extracellular determinant ofthe P-gp that is specifically France) for K562adr and 0.8 @g/mlTaxol (a gift from Dr. F. Picot, Institut de expressed
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