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Uptake of the Noncytotoxic Transport Probe Procainamide in the Chinese Hamster Ovary Model of Multidrug Resistance1

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Uptake of the Noncytotoxic Transport Probe Procainamide in the Chinese Hamster Ovary Model of Multidrug Resistance1 (CANCER RESEARCH 52. 3539-3546. July 1. 1992] Uptake of the Noncytotoxic Transport Probe Procainamide in the Chinese Hamster Ovary Model of Multidrug Resistance1 K. V. Speeg, Jr.,2 Catherine deLeon, and William L. McGuiret Department of Medicine, Divisions of Gastroenterologe/Nutrition [K. V. S., C. D.J and Oncology [W. L. M.], The University of Texas Health Science Center at San Antonio and Audie Murphy VA Hospital, San Antonio, Texas 78284 ABSTRACT to be a normal constituent of cells in organs known to secrete organic cations (i.e., renal proximal tubule, hepatocyte bile Many of the cytotoxic substrates of the multidrug transporter are canaliculus, and adrenal medulla) (7-9), we used noncytotoxic organic cations. Cimetidine, procainamide, and tetraethylammonium bro mide were used in a Chinese hamster ovary model of multidrug resistance, probes of organic cation secretion (10, 11), which is generally to study handling of noncytotoxic cationic transport probes. Cimetidine considered to be driven by electrochemical gradients rather and procainamide, but not tetraethylammonium, accumulated to a greater than by an ATPase (12), to determine whether these probes extent (5-fold) in the sensitive CHOAUXB1 (AB) cell line than in the might be substrates for gp-170 or whether this secretory mech resistant ( 11"( 5 (C5) cell line. Accumulation of both cimetidine and anism could be characterized in MDR cells. procainamide was significantly increased by verapamil in CS but not AB. Procainamide accumulation in both AB and CS was temperature depend ent and occurred by passive diffusion. Diltiazem, nifedipine, rifampin, MATERIALS AND METHODS tamoxifen, rhodamine, and ethidium also increased procainamide accu Materials. ['H]Cimetidine (specific activity, 20 Ci/mmol) was pur mulation in C5 but not AB. Azide in glucose-free medium increased chased from Amersham Corp. (Arlington Heights, IL); ['Hjprocaina- procainamide accumulation in CS, and this was reversed when glucose, mide (specific activity, 48 Ci/mmol) and ['H]TEA (specific activity, 16 but not 3-0-methylglucose, was added. Procainamide efflux rates were Ci/mmol) were custom synthesized by Amersham. Verapamil, dilti- similar in AB and CS and not affected by verapamil or azide. The initial azem, nifedipine, rifampin, tamoxifen, rhodamine, ethidium bromide, rate of procainamide uptake was higher in AB than in CS, and both procainamide, 3-0-methylglucose, and sodium azide were from Sigma verapamil and azide increased the initial rate of procainamide uptake in Chemical Co. (St. Louis, MO). GBSS and glucose-free GBSS were CS. Thus, differences in accumulation of the noncytotoxic transport probe prepared in 10-liter batches, filtered through 0.22-Mm filters, and stored procainamide in the colchicine-sensitive and colchicine-resistant compo in sterile bottles. Phosphate-buffered incubation medium contained (in nents of the Chinese hamster ovary cell line mimic the accumulation of HIM):sodium chloride, 139; dibasic potassium phosphate, 2.5; magne known cytotoxic substrates for the multidrug transporter, such as colchi- sium sulfate, 1.2; calcium chloride, 2.0; glucose, 5.5; L-alanine, 6.0; cine, vinblastine, and doxorubicin. The differential accumulation of pro sodium citrate, 1.0; and sodium lactate, 4.0. The standard pH was 7.4. cainamide is due to differences in rates of drug influx, rather than efflux. Cell Culture. The adenosine-, thymidine-, and glycine-requiring aux- Since procainamide influx is passive and decreased accumulation in the otroph AB and its colchicine-resistant mutant C5 were obtained from resistant line appears to parallel M, 170,000 glycoprotein presence and Dr. Victor Ling of the Ontario Cancer Institute (Toronto, Canada) activity, we would speculate that decreased procainamide accumulation (13). Cells were maintained at 37°Cin 5% CO2-95% air, in monolayer may be due to an indirect effect of the M, 170,000 glycoprotein, such as culture, in Mminimum essential medium (with ribonucleosides and its effect on intracellular pH. deoxyribonucleosides) supplemented with 10% fetal bovine serum, 10 mM iV-(2-hydroxyethyl)piperazine-jV'-(2-ethanesulfonic acid) buffer, INTRODUCTION pH 7.4, 0.2% sodium bicarbonate, and 40 ¿ig/mlgentamicin. Stock cultures of C5 were maintained in the presence of colchicine (1 jig/ml), Emergence of drug-resistant cancer cells during the course of to prevent growth of revenants. C5 grown in colchicine-containing chemotherapy is considered a major cause of treatment failure. medium until the time of experiments gave results identical to C5 In in vitro cancer models, MDR' occurs following the amplified maintained in colchicine-free medium. To determine the toxicity of expression of the mdr gene and the appearance of its product, procainamide or cimetidine on AB and C5, cells were grown for 1 week gp-170, in the plasma membrane (1-3). The drugs to which in medium containing either 100 MMprocainamide or cimetidine (sub culture to confluence). These cultures were without evidence of toxicity. resistance develops include the organic cations actinomycin, The human breast cancer line MDA-MB-231, which is sensitive to doxorubicin, and vinblastine. Evidence suggests that gp-170 Adriamycin, and MDA-A1R, which is resistant to Adriamycin, were acts as an efflux pump (3). Other organic cations, including grown as previously described (14). The human cell line KB-3-1, which calcium channel antagonists, calmodulin inhibitors, rifampin, is sensitive to vinblastine, and KB-V-l, which is resistant to vinblastine, and fluorescent dyes, have been reported to increase accumu were generously provided by Dr. Dan Von Hoff (University of Texas lation of cytotoxic drug in multidrug-resistant cells, and some Health Science Center at San Antonio, TX) and were grown as previ have been demonstrated to increase cytotoxicity, reversing the ously reported (6, 15). resistance phenotype (4-6). Since gp-170 has also been found Uptake and Efflux Experiments. Experiments were in 24-well plates (Costar, Cambridge, MA), using confluent cells. Each data point was Received 10/25/91; accepted 4/23/92. in triplicate and corrected for an identically treated well without cells. The costs of publication of this article were defrayed in part by the payment For uptake experiments, medium was removed and the cell sheet was of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. rinsed with GBSS prior to addition of radioactive drug. Following ' This work was supported by NIH Grant CA30195 and the Veterans Admin incubation, radioactive medium was rapidly aspirated and the cell sheet istration Research Service and was reported, in part, at the meeting of the was rinsed once with 2 ml of cold 0.9% NaCl. Cells were then dissolved American Federation for Clinical Research, May 1988 (34). 2To whom requests for reprints should be addressed, at Department of in l N NaOH, and radioactivity was quantitated in acidified aqueous Medicine/Gastroenterology, University of Texas Health Science Center at San counting solution (Amersham), by liquid scintillation counting. Varia Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78284. tions for individual experiments are given in "Results" and the figure 'The abbreviations used are: MDR, multidrug resistance; CHO, Chinese legends. For efflux experiments, following incubation with radioactive hamster ovary; AB, Chinese hamster ovary cell line CHOAUXB1; C5, Chinese hamster ovary cell line CH"C5; GBSS, Grey's balanced salt solution; TEA, drug to establish equilibrium, medium was rapidly removed, the cell tetraethylammonium; gp-170, M, 170,000 glycoprotein. sheet was rinsed with 2 ml of GBSS, and 1 ml of efflux medium ' Deceased. (generally GBSS) was added. At the appropriate times, cells were 3539 Downloaded from cancerres.aacrjournals.org on October 6, 2021. © 1992 American Association for Cancer Research. ORGANIC CATION UPTAKE BY CHO CELLS more procainamide in the presence of verapamil (Fig. 2, B and C). The effect was not as striking in the KB line as with the CHO line. In Adriamycin-sensitive and -resistant MDA cells, we found neither a difference in procainamide accumulation nor an effect of verapamil (data not shown). Time Course of | 11|( inieiidiiH' Accumulation. AB and C5 were incubated at 23°Cwith 70 n\i ['HJcimetidine, in the absence or presence of 100 ^M verapamil. Both AB and C5 progressively accumulated cimetidine, with the sensitive AB line having approximately 5-fold more at 20 min than did C5 (0.49 versus 0.09 fmol/^g DNA). Verapamil did not signifi cantly influence the accumulation of cimetidine by AB but caused a marked increase in cimetidine accumulation in C5, producing levels similar to those in the AB cell line. Tetraethylarnmonium Bromide and Partition Coefficients. | !l I] TEA, a quaternary amine which is virtually always charged, is secreted by the organic cation secretory mechanism in the renal tubule. AB and C5 were incubated with ['H]TEA at 23°C,but we were unable to demonstrate any accumulation in either cell with time or varying concentration, whether in the absence or in the presence of 100 ^M verapamil (data not shown). Parti tioning between octanol and GBSS, pH 7.4, at 23°Cfor these Fig. 1. Time course of procainamide accumulation in AB. the cell line sensitive to colchicine ill- or C5, the cell line resistant to colchicine (B). Procainamide (SO MMiwas added in the absence or presence of 100 ,.Mverapamil. in Dulbecco's modified Eagle medium, at
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