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Modulation of Cytotoxicity of Menadione Sodium Bisulfite Versus Leukemia L1210 by the Acid-Soluble Thiol Pool1

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Modulation of Cytotoxicity of Menadione Sodium Bisulfite Versus Leukemia L1210 by the Acid-Soluble Thiol Pool1 [CANCER RESEARCH 45, 5257-5262, November 1985] Modulation of Cytotoxicity of Menadione Sodium Bisulfite versus Leukemia L1210 by the Acid-soluble Thiol Pool1 StevenA.Akman,2MarianDietrich,RowanChlebowski,PhyllisLimberg,andJeromeB.Block Division of Medical Oncology, UCLA School of Medicine, Harbor-UCLA Medical Center, Terranee, California 90509 ABSTRACT growth inhibition by menadione is not known. Due to its quinone structure, menadione participates as a powerful oxidation-reduc We investigated the mechanism of antitumor activity of the tion agent in oxygen-consuming electron transfer reactions cat water-soluble derivative of menadione, menadione sodium bisul alyzed by microsomal enzymes (8-12). Menadione semiquinone fite (vitamin KJ, versus murine leukemia L1210. Vitamin Ka, in free radical is generated during reduction of the quinone (9,10); concentrations >27 ¿¿M,causedtime- and concentration-depend this radical is short lived, producing Superoxide radicals (9, 10, ent depletion of the acid-soluble thiol (GSH) pool. Maximal GSH 12, 13). The consequences of menadione reduction have been depletion to 15% of control occurred at 45 /¿Mvitamin«3.Vitamin invoked as the cause(s) of menadione toxicity in normal hepa- Ka-mediated GSH depletion and vitamin Ks-mediated growth tocytes (8, 13) and neutrophils (14), and menadione is thought inhibition were abrogated by coincubation with 1 mw cysteine or to be responsible for: (a) depletion of NAD(P)H with subsequent 1 mw reduced glutathione but not by 1 mw ascorbic acid or 180 depletion of mitochondrial ATP (15); (b) Superoxide and peroxy fiM a-tocopherol. Low concentrations of vitamin Ka (9-27 ¿¿M)radical generation, causing peroxidative damage (13, 16, 17); elevated both the GSH pool and the total glutathione pool, the and (c) depletion of cellular GSH3 (13, 14). The data presented latter to a greater degree. Vitamin Ka also caused an increased in this paper suggest that menadione potently depletes tumor rate of Superoxide anióngeneration by L1210, maximal at 45 I*M cell GSH and NADP pools and that acid-soluble thiols are impor vitamin Ka (300% of control), and a concentration-dependent tant modulators of menadione antitumor activity. depletion of the reduced nicotinamide adenine dinucleotide phos phate (NADPH) and total nicotinamide adenine dinucleotide phos phate (NADP) pools. Forty-fifty % depletion of the NADPH pool MATERIALS AND METHODS occurred after exposure to 27 /¿Mvitamin«3and 100% occurred Chemicals and Reagents. L-Cysteine, vitamin K3, ascorbic acid, at 36 nu vitamin Ka; 27 /tw vitamin «3isa nontoxic concentration NADPH, NADP+, reduced glutathione, Superoxide dismutase (EC of vitamin Ka. Loss of NADPH and total NADP was prevented 1.15.1.1, from bovine blood), glutathione reductase (EC 1.6.4.2), and all by coincubation with 1 mw cysteine but not by coincubation with reagents for the assay for pyridine nucleotides were purchased from ascorbic acid or a-tocopherol. We conclude that tumor cell Sigma Chemical Co. (St. Louis, MO). a-Tocopherol:polyethylene glycol growth inhibition by vitamin Kais modulated by acid-soluble thiols 100:succinate was purchased from Eastman Chemical Co. (Kingsport, and may be caused by GSH pool and/or NADPH depletion. TN). This derivative of a-tocopherol is soluble in boiling water at concen Toleration of partial NADPH depletion by L1210 cells may indi trations «50 mW. DTNB was purchased from K and K Laboratories cate that a threshold level of NADPH loss of >50% is necessary (Hollywood, CA). Lapachol [1,4-naphthoquinone-2-hydroxy-3-(methyl- for toxicity. NADPH depletion may be a toxic effect common to 2-butenyl), NSC 11905] and dichlorolapachol [2-hydroxy-3-(3,3-dichlo- quinone drugs. Equitoxic concentrations of vitamin K;1, phyllo- roallylH ,4-naphthoquinone, NSC 125771] were received as gifts from the Drug Synthesis and Chemistry Branch, Division of Cancer Treatment, quinone, lapacho!, dichlorolapachol, and doxorubicin caused National Cancer Institute, Bethesda, MD. Doxorubicin was obtained from L1210 NADPH pools to deplete to 30 ±10 (SD), 60 ±10, 60 ± Adria Laboratories (Columbus, OH). Phylloquinone (Aqua Mephyton) was 11, and 80 ± 12% of control, respectively. In contrast, GSH obtained from Merck, Sharpe, and Dohme (Westpoint, PA). All chemicals depletion may not be a common mechanism of toxicity. Of these were used as received. quiñones,only vitamin K3caused significant GSH depletion when Cell Culture. Leukemia L1210, a murine leukemia maintained in long studied in equitoxic concentrations. term liquid suspension culture, was used in all experiments. L1210 cells were maintained in 15-ml tissue culture flasks (Falcon Plastics, Oxnard, CA) at an initial concentration of 100,000 cells/ml using Roswell Park INTRODUCTION Memorial Institute Medium 1640 (Grand Island Biological Co., Grand Island, NY) supplemented with 15% heat-inactivated (56°Cfor 30 min) The naphthoquinone derivative menadione (2-methyl-1,4- fetal bovine serum, penicillin (100 units/ml), streptomycin (100 ng/m\), naphthoquinone) has been shown to inhibit the growth of tumor and i -glutamina (2 mw) at 37°C in an atmosphere containing 5% CO2 cells in vitro (1-6). In the human tumor stem cell soft agar cloning and 95% air. Cultures were fed twice weekly and were in logarithmic assay (7), menadione causes inhibition of clonal growth of a wide growth phase at the time of all experimental studies. variety of tumor cell types (3). Its anticancer activity with this Growth inhibition by the drugs reported in these studies were observed by the dose-response method described previously (18). Briefly experi assay is comparable or superior to currently used standard ments were carried out in 15-ml tissue culture flasks. Supplemented chemotherapeutic agents, such as doxorubicin. Menadione is in Roswell Park Memorial Institute Medium 1640, drug(s), and cells in use in early trials in patients with advanced cancer (2) with the logarithmic growth were added to the flasks and incubated at 37°C in antimetabolite 5-fluorouracil. The mechanism of tumor cell 'The abbreviations used are: GSH, total-acid soluble thiols, reduced form; 1Supported in part by a grant from the California Institute For Cancer Research. vitamin K3. menadione sodium bisulfite; GSSG, total acid soluble thiols, oxidized 2To whom requests for reprints should be addressed. form; DTNB, 5,5'-dithiobis-<2-nitrobenzoic acid); SOD, Superoxide dismutase (EC Received 9/4/84; revised 7/24/85; accepted 7/26/85. 1.15.1.1). CANCER RESEARCH VOL. 45 NOVEMBER 1985 5257 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 1985 American Association for Cancer Research. MODULATION OF REDUCED GLUTATHIONE BY VITAMIN an atmosphere of 5% CO2 with 95% air. Cells were added at an initial centrifugation at 280 x g for 10 min at 4°C. Cells were then washed concentration of 100,000 cells/ml. Drugs were diluted in Dulbecco's three times in ice-cold Dulbecco's phosphate-buffered saline (19) supple phosphate-buffered saline (Grand Island Biological Co.) (19). Each ex mented with 10 mM glucose. After cells were washed, NADPH pools perimental point was derived from triplicate cultures. After 16 h of were determined on cells which were extracted with 300 n\ of tee-cold incubation, cells were washed free of drug with two washes of Ros well 0.5 N KOH in 50% ethanol, heated for 5 min at 90°C, recooled to 0°C, Park Memorial Institute Medium 1640 and incubated in fresh supple and neutralized with 0.5 M triethanolamine in 0.4 M dibaste potassium mented media. Cells were fed with new media on day 4. Cell counts phosphate. NADPH in the neutralized alkaline extracts was converted to were performed on days 4 and 7 on a Model ZBI Coulter Counter NADP* prior to assay by addition of 10 MM GSSG and 0.2 unit of (Coulter Electronics, Hiateah, FL). glutathione reductase (Sigma type III, from yeast) and incubation at 37°C Acid-soluble Thiols. Acid-soluble thiol pools were determined for for 30 min. The extracts were then acidified with ice-cold 2 M m- aliquot s of 10 to 50,000,000 cells by modification of the method of phosphoric acid, centrifuged at 15,000 x g for 5 min to remove protein, Beutter ef al. (20). Cells were cooled on tee for 5 min and harvested by and reneutralized with 2 N KOH in 0.3 M N-morpholinopropanesulfonic centrifugation at 280 x g at 4°C. After removal of aliquots for protein acid. NADP4 pools were determined on cells extracted with 0.2 M m- assay by the method of Bradford (21), the resultant cell pellets were phosphoric acid. After centrifugation at 1500 x g and neutralization of layered onto 600 n\ of 0.14 M m-phosphoric acid containing 4.6 HIM the supematants with 1 N KOH in 0.15 M W-morpholinopropanesulfonic EDTA and 3.47 M sodium chloride, overlaid with 500 ¿ilof silicone fluid acid, NADP* content was determined by measuring the rate of increase DC550 (Dow Chemical, Midland, Ml):light mineral oil, 84:16, in 1.5-ml of absorbance of 570 nm light due to reduction of thiazolyi blue in the Eppendorf centrifuge tubes. Tubes were centrifuged at 15,000 x g for cycling system containing 300 //I of the cell extracts, 0.1 N Tris-HCI (pH 10 s in a microcentrifuge (Fisher Scientific, Tustin, CA), allowing 100% 7.8), 5 mM glucose 6-phosphate, 5 mM MgSO,, 0.8 mM phenazine of the cells to migrate into the m-phosphoric acid layer, with less than methylsulfate, 0.2 mM thiazolyi blue, and 0.3 unit glucose-6-phosphate 2% contamination by supernatant (22, 23). Supernatant and oil layers dehydrogenase (Sigma type IX, from yeast). Each assay was carried out were removed and cell pellets were dispersed in the m-phosphoric acid at 25°C in cuvets containing 1.2 ml total volume.
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