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Reversal of Vinca Alkaloid Resistance but Not Multiple Drug Resistance in Human Leukemic Cells by Verapamil1

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Reversal of Vinca Alkaloid Resistance but Not Multiple Drug Resistance in Human Leukemic Cells by Verapamil1 [CANCER RESEARCH 46, 778-784, February 1986] Reversal of Vinca Alkaloid Resistance but not Multiple Drug Resistance in Human Leukemic Cells by Verapamil1 William T. Beck,2 Margaret C. Cirtain, A. Thomas Look, and Richard A. Ashmun Departments of Biochemical and Clinical Pharmacology [W. T. B., M. C. C.] and Hematology-Oncology [A, T.L, R. A. A.], St. Jude Children's Research Hospital, Memphis, Tennessee 38101 ABSTRACT erties of tumor cells that have been selected for resistance to We examined the ability of verapamil, a Ca2+ channel blocker, one of a few antitumor drugs, such as Vinca alkaloids, anthra- cyclines, epipodophyllotoxins, and other "natural products" or to overcome Vinca alkaloid and multiple drug resistance in our their semisynthetic derivatives. This pattern of resistance has CEM/VLB10o and CEM/DOX human leukemic lymphoblasts. Compared with the parent CCRF-CEM cells, CEM/VLB100 cells been substantiated in experimental tumor systems both in vivo (1-4) and in vitro (5-11), and various pharmacological, biochem are ~200- to 800-fold resistant to vinblastine and express cross- resistance to vincristine, doxorubicin, and other "natural product" ical, and molecular alterations have been linked with it (6). For example, a high molecular weight glycoprotein has been found drugs, as determined by comparing 50% inhibitory concentra tions in a 48-h growth inhibition assay. Verapamil (10 MM) de on the surfaces of MDR cell lines of rodent (12, 13) and human (14) origin. However, despite clinical indications of MDR in pa creased the 50% inhibitory concentrations for Vinca alkaloids in tients with (usually) advanced neoplastic disease, such biochem CEM/VLB100 cells by =75- to 85-fold but caused only slight («2- ical "markers" on the tumor cells from these individuals have yet to 5-fold) decreases in 50% inhibitory concentrations for anthra- cyclines, epipodophyllotoxins, and other tubulin-binding drugs to be consistently shown to be linked to this phenomenon. Recent pharmacological studies in experimental systems have (colchicine and podophyllotoxin). Qualitatively similar results were obtained with doxorubicin-resistant cells, termed CEM/ sought to circumvent MDR with the goal of applying this infor DOX; verapamil caused a 19-fold increase in doxorubicin toxicity mation in treatment strategies for unresponsive patients (15). but 67- and 3500-fold increases in the toxicities of vinblastine Foremost among these efforts have been the studies of Tsuruo ef al. (16-22) and others (23, 24), showing that Ca2+ channel and vincristine, respectively. These results indicate that the effect blockers, such as verapamil, and calmodulin antagonists, such of verapamil is relatively greater for Vinca alkaloids, with less as trifluoperazine, can reverse alkaloid and anthracycline resist pronounced effects for the other natural product drugs against which these cells express multiple drug resistance. In flow cy- ance in vitro and in vivo. This subject has been reviewed recently (25). tometric studies, individually nontoxic or minimally toxic concen During the course of our investigations, we found that vera trations of vinblastine plus verapamil caused measurable accu pamil did not greatly reverse MDR but produced a rather specific mulation in the G2 + M phase as early as 4 h after the drug and rapid enhancement of Vinca alkaloid cytotoxicity in our combination was added to cultures of CEM/VLB100 cells; this alkaloid- and anthracycline-resistant human leukemic cell lines; finding correlated with a comparable increase in the number of our results are the focus of this paper. A preliminary account of cells in mitosis and measurable decreases in the total number of some of this work has been presented (26). cells. Since similar effects on cell cycle distribution, percentage of cells in mitosis, and cell number were seen when CEM/VLBioo MATERIALS AND METHODS cells were treated with toxic concentrations of vinblastine alone, we conclude that the primary toxicity of the vinblastine-verapamil Cells and Culture Conditions. CCRF-CEM human leukemic lympho combination stems from the alkaloid. Further, the rapid lytic blasts (CEM) and their drug-resistant variants were grown as described effect of the drug combination was associated with cellular earlier (14). Drug-resistant sublines were selected by growth in the vacuolization. The vacuoles did not stain for lipids, and increases continuous presence of sublethal concentrations of drug. After 1-2 in their number were evident within 2 to 4 h after drug treatment. months, cells were exposed to drug on an intermittent basis, usually only 3-4 days per week. The following cell lines were selected: CEM/ We suggest that verapamil enhances Vinca alkaloid cytotoxicity by altering "cryptic" cytotoxic targets, possibly related to these VLB,oo, «200- to 800-fold resistant to VLB (14); CEM/DOX, «70- to 190-fold resistant to DOX; CEM/ara-C, -3000-fold resistant to ara-C; vacuoles, through some as yet undefined membrane effect. and CEM/MTX, »1333-fold resistant to MTX. Quantitation of Drug Effects. The growth-inhibitory effects of drugs, INTRODUCTION either alone or in combination, were assessed by plating cells in multiwell MDR3 is a term used to describe the cross-resistance prop- dishes (Costar No. 3524) at a final density of =2.5-3 x 105/ml. Drug solutions were made in 0.9% NaCI solution and were «10% of the final Received 6/17/85; accepted 11/5/85. volume of the cell suspension; epipodophyllotoxins were dissolved in 1Support was provided in part by Research Grant CA-30103 and Cancer Center dimethyl sulfoxide, the final concentration of which («0.69%) had no Support (CORE) Grant CA-21765 from the National Cancer Institute, Bethesda, effect on cell growth (27). MD, and by American Lebanese Syrian Associated Charities. 2 To whom requests for reprints should be addressed. Cell numbers were determined with a Coulter Counter (Model ZBI), 3 The abbreviations used are: MDR, multiple drug resistance; VLB, vinblastine using a Channelyzer to distinguish cells from debris. The ICsowas defined sulfate; VCR. vincristine sulfate; DOX, doxorubicin; DNR, daunorubicin; VM-26, teniposide (4'-dimethylepipodophyllotoxinthenylidene-iì-o-glucoside); VP-16-213, as the concentration of drug that inhibits the 48-h cell growth by 50%, etoposide (4'-dimethylepipodophyllotoxinethylidene-fi-D-glucoside); CLC, colchi compared with untreated controls. The fold decrease in ICsowas deter cine; POD, podophyllotoxin; MTX, methotrexate; ara-C, 1-0-D-arabinofuranosylcy- mined by dividing the IC50for the controls by that for verapamil-treated tosine; IC»,concentration that inhibits 48-h cell growth by 50%. cells. CANCER RESEARCH VOL. 46 FEBRUARY 1986 778 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1986 American Association for Cancer Research. SELECTIVE ENHANCEMENT OF VINCA ALKALOID CYTOTOXICITY BY VERAPAMIL Flow Cytometry. After exposure to drugs for different times, cells their IC50 values. Thus, in the presence of verapamil, CEM/ were harvested for flow cytometry. DNA staining with propidium iodide, VLB10ocells largely retain MDR despite increased susceptibility generation of DNA histograms, and analysis of the percentage of cells in to Vinca alkaloid toxicity. It may be of importance that the ability Go-G,, S, and G2-M phases of the cell cycle were done as described of verapamil to enhance drug cytotoxicity is roughly proportional earlier (28). The percentage of mitotic cells for each sample was deter mined in acetocarmine-stained preparations (28). Histochemical staining to the degree of resistance of the cells. of cytospin preparations was done with an automated Ames Hema-Tek Effect of Verapamil on Drug Cytotoxicity of Other Drug- slide stainer. resistant CEM Cell Lines. It was important to determine if the Chemicals and Supplies. VLB and VCR were obtained from Eli Lilly verapamil effect was restricted to Vinca alkaloids in alkaloid- and Co. (Indianapolis, IN), DOX and DNR were from Adria Laboratories resistant cells or if it extended to cells selected for primary (Wilmington, DE), VM-26 and VP-16-213 were from Bristol Laboratories resistance to other drugs. Shown in Table 2 are results of (Syracuse, NY), and CLC and POD were purchased from Sigma Chemical experiments that test the effect of verapamil on our CEM/DOX Co. (St. Louis, MO). Tissue culture media and fetal bovine serum were cell line, which is =70- to «190-fold more resistant to DOX than obtained from KC Biologicals (Lexena, KS) and Flow Laboratories is the parent line and »68-and «238-fold cross-resistant to VLB (McLean, VA), respectively, and tissue culture plasticware was from standard sources. and VCR, respectively. Verapamil clearly enhanced the cytotox icity of DOX against these cells in a progressive, concentration- dependent manner, but the effect was less striking than observed RESULTS for Vinca alkaloids against CEM/VLB100 cells. The MDR phenotype of CEM/DOX cells is characterized in Effect of Verapamil on MDR in CEM/VLB100 Cells. We part by cross-resistance to DNR, Vinca alkaloids, and epipodo showed previously that verapamil effectively enhanced the cy- phyllotoxins (30). Addition of verapamil with Vinca alkaloids to totoxicity of VLB in the VLB-resistant CEM/VLB100 cells (29): cultures of CEM/DOX cells produced the rather unexpected increasing concentrations of verapamil shifted the VLB dose- results shown in Table 2. Not only did verapamil cause an response curve to the left; at 10 MMverapamil, the IC50for VLB apparent dose-related reduction
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