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(The FASEB Journal. 1998;12:1627-1633.)
© 1998 FASEB

RESEARCH COMMUNICATION

Chemically induced isomerization and differential uptake modulate retinoic acid disposition in HL-60 cells

C. Lanversa, G. Hempela, G. Blaschkeb and J. Boosa,1

a Department of Pediatric Hematology and Oncology, University of Münster, 48149 Münster, Germany
b Department of Pharmaceutical Chemistry, University of Münster, 48149 Münster, Germany


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The successful introduction of 13-cis-retinoic acid (13-cis-RA) and all-trans-retinoic acid (all-trans-RA) in the chemoprevention and treatment of cancer along with the discovery of different retinoic acid receptors transactivated by different retinoic acid isomers resulted in a number of in vitro studies of the antitumor effects of single retinoic acid isomers. Since the formation of retinoic acid isomers with different receptor affinities might modulate retinoic acid response in vitro, we determined retinoic acid disposition in HL-60 cells and cell culture medium during incubation with 13-cis-, 9-cis-, and all-trans-RA. In medium, retinoic acids underwent a thiol-radical mediated isomerization resulting in a mixture of 13-cis-, 9-cis-, 9,13-di-cis-, and all-trans-RA. Except for the 9,13-di-cis-RA, all isomers generated in medium were also detected in HL-60 cells. Whereas 9-cis-RA and 13-cis-RA showed similar cellular pharmacokinetics, all-trans-RA reached about fourfold higher concentrations in HL-60 cells compared to 9-cis-RA and 13-cis-RA. Due to its better uptake, all-trans-RA became the main isomer within cells as it was formed in the medium when incubated with 13-cis-RA and 9-cis-RA. Thus, due to the simple chemically induced isomerization and its profound influence on cellular retinoic acid concentrations, studies of the efficacy of single retinoic acid isomers in vitro should be interpreted with caution.—Lanvers, C., Hempel, G., Blaschke, G., Boos, J. Chemically induced isomerization and differential uptake modulate retinoic acid disposition in HL-60 cells. FASEB J. 12, 1627–1633 (1998)


Key Words: cellular pharmacokinetics • retinoid X receptor • 13-cis-RA • retinoic acid receptor


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
THE NATURAL RETINOIC ACID (RA)2 isomers all-trans-RA, 9-cis-RA, and 13-cis-RA are part of a complex signaling system that is essential for the normal development and homeostasis of vertebrates (1). The retinoic acid response pathways are mediated by two subtypes of nuclear receptors, the retinoic acid receptor (RAR) and the retinoid X receptor (RXR), which function as dimeric ligand dependent transcription factors (2, 3). The retinoic acid isomers differ in their affinities for the two types of retinoic acid receptors. Whereas all-trans-RA only transactivates the RAR, 9-cis-RA binds to both types of retinoic acid receptors. 13-Cis-RA, since it does not bind to the retinoic acid receptors with high affinity, is supposed to be transformed into retinoic acid receptor binding ligands in vivo (4, 5).

Besides their fundamental role in normal cell development, retinoids influence the growth and differentiation of a variety of transformed and neoplastic cells (6). In vitro retinoic acids induce neuronal differentiation in neuroblastoma cells (7, 8), myeloid differentiation in HL-60 myeloid and NB4 promyelocytic leukemia cell lines (9–11), and suppress squamous cell differentiation in squamous cell carcinoma (12). In vivo 13-cis-RA combined with interferon {alpha} is effectively used to treat squamous cell carcinoma of the skin and cervix and in the prevention of second primary tumors associated with head and neck cancers (13–15). Differentiation of the leukemic clone along the granulocytic pathway by all-trans-RA results in complete remission in 80–90% of patients with acute promyelocytic leukemia (APL) (16, 17).

Besides the tissue and growth specific expression of distinct retinoic acid receptors, the effects of retinoic acids are also determined by their uptake and metabolism in target cells. In APL, response to all-trans-RA in vivo correlated with its uptake by leukemic blasts in vitro (18). Next to oxidation, the retinoic acid isomerization is considered another important metabolic pathway, which allows cells to modulate retinoic acid response. So far, however, no enzyme has been identified that controls retinoic acid isomerization. Instead, thiol group containing compounds were shown to catalyze the isomerization of 13-cis-RA, 9-cis-RA, and all-trans-RA, resulting in a mixture of 13-cis-, 9-cis-, 9,13-di-cis-, and all-trans-RA ( Fig. 1) (19–22). As thiol group containing compounds are ubiquitous in biological fluids, this process has been considered to be responsible for retinoic acid isomerization in vivo. Moreover, due to the presence of thiol compounds, this process is likely to take place in cell culture medium as well and was observed in control experiments of in vitro studies of the metabolism of all-trans-RA by tumor cells (23).



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  		Figure 1. Thiol-mediated isomerization of 13-cis-RA, 9-cis-RA, and all-trans-RA (20, 22).

However, despite the large number of in vitro studies, isomerization of retinoic acids in cell culture medium has not been examined for all three retinoic acid isomers. Therefore, during incubation with 13-cis-RA, 9-cis-RA, and all-trans-RA, we determined the retinoic acid disposition in the cell culture medium and in the human HL-60 myeloid leukemia cell line, a model that has already been extensively studied for retinoic acid effects.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Materials
All-trans-RA and 13-cis-RA were purchased from Sigma (Deisenhofen, Germany). 9-Cis-RA (Ro 04–4079), all-trans-retinol (Ro 01–4955), and acitretin (Ro 10–1670) were generously provided by Hoffmann-La Roche (Basel, Switzerland). The thiol group blocking agent, N-ethylmaleimide (NEM), and melatonin were purchased from Sigma (Deisenhofen, Germany); L-ascorbic acid was obtained from Merck (Darmstadt, Germany). Purity of retinoic acids, determined by high-pressure liquid chromatography (HPLC) analysis, was >98%.

Each retinoid was individually dissolved in ethanol 100% to produce stock solutions of 1 mg/ml. Stock solutions of NEM and melatonin were prepared in 100% ethanol. L-Ascorbic acid was dissolved in deionized water. The concentrations of ethanol in cell culture medium never exceeded 0.1%.

Fetal calf serum (FCS), penicillin, streptomycin, and RPMI 1640 medium containing 2 mM L-glutamine were obtained from Gibco BRL Life Technologies (Eggenheim, Germany). 2-Propanol, 1-heptanol, n-hexane, glacial acetic acid, and dichloromethane were obtained from Baker (Gross-Gerau, Germany) and were of HPLC grade. The remaining chemicals were purchased from Merck (Darmstadt, Germany) and were of analytical grade.

Laboratory precautions
To avoid photoisomerization, all handling with retinoids was performed under subdued light, and flasks containing retinoids were covered with aluminum foil.

Cell culture
HL-60 myeloid leukemia cells (24) were obtained from the European Collection of Cell Cultures (Salisbury, U.K.) and tested negative for mycoplasmal infection. Cells were grown in RPMI 1640 medium supplemented with L-glutamine (2 mM), heat-inactivated FCS (10%), penicillin (100 U/ml), and streptomycin (100 µg/ml) in a humidified atmosphere with 5% CO2 at 37°C. To maintain exponential growth, cells were subcultured every 3 days.

Extraction of retinoids
After protein precipitation with 500 µl of an ethanolic solution of the internal standard acitretin and 500 µl of saturated ammonium sulfate solution, 500 µl medium or 5 x 106 to 10 x 106 cells were extracted by liquid–liquid extraction with a mixture of n-hexane, dichloromethane, and 2-propanol. The organic layer was removed, dried with anhydrous sodium sulfate, and evaporated under a stream of nitrogen. The residue was dissolved in 100 µl n-hexane and a 50 µl aliquot was analyzed by HPLC.

HPLC analysis
The HPLC system consisted of an LKB 2150 HPLC pump and an LKB 2151 Variable Wavelength UV detector (Pharmacia Biosystems, Freiburg, Germany).

Separation was performed on a silica gel column (Nucleosil 100, 5 µm, 200x4 mm I.D.) (Macherey and Nagel, Düren, Germany) fitted with a silica gel guard column (Nucleosil 100, 5 µm, 15 mm x 4 mm I.D.) at a flow rate of 1 ml/min. The mobile phase consisted of n-hexane, 2-propanol, and glacial acetic acid (400:1:0.27). Retinoids were determined by UV detection at a wavelength of 350 nm with limits of detection of 1.7 nM for retinoic acids and 35 nM for all-trans-retinol (25).

To record all double-bond retinoic acid isomers that might be generated during the incubation, retinoic acid isomers were also separated on two silica gel adsorption columns (Nucleosil 100, 5 µm, 200x4 mm I.D.) connected in series and fitted with a silica gel guard column (Nucleosil 100, 5 µm, 15 mm x 4 mm I.D.) following a method described by Urbach and Rando (22). The retinoic acid isomers were eluted with n-hexane, 1-heptanol (199:1, v/v) containing 10 mM trichloroacetic acid at a flow rate of 1.5 ml/min, and detected at a wavelength of 350 nm with a limit of detection of 20 nM.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Incubation of all-trans-RA, 13-cis-RA, and 9-cis-RA under cell culture conditions used frequently for cultivation of HL-60 cells and other leukemic cells resulted in a rapid degradation of the retinoic acids by oxidation and isomerization. Their decline followed first-order kinetics, with 13-cis-RA possessing the fastest (t50%: 1.6±0.06 days), all-trans-RA an intermediate (t50%: 2.4±0.13 days), and 9-cis-RA the slowest degradation rate (t50%: 2.86±0.16 days). Isomerization always resulted in a mixture of 13-cis-RA, 9-cis-RA, 9,13-di-cis-RA, and all-trans-RA, regardless of the retinoic acid isomer incubated ( Fig. 2). Within 7 days, an equilibrium was reached at 14.7 ± 1.7% 13-cis-RA, 38.2 ± 2.8% 9,13-di-cis-RA, 20.4 ± 3.1% 9-cis-RA, and 26.7 ± 3.5% all-trans-RA. The formation of retinoic acid isomers from 13-cis-RA, 9-cis-RA, and all-trans-RA was linear over a range of 10 nM to 10 µM with coefficients of correlation >0.98, which supports the theory of chemically induced isomerization ( Fig. 3).



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  		Figure 2. Degradation of 13-cis-RA (A), 9-cis-RA (B), and all-trans-RA (C) under cell culture conditions. 10 µM of 13-cis-RA, 9-cis-RA, and all-trans-RA were incubated in RPMI 1640 medium supplemented with 10% heat-inactivated FCS, glutamine, and antibiotics in a humidified atmosphere at 37°C. At the indicated times, medium was analyzed for retinoic acid isomers by HPLC. Experiments were repeated in triplicate with each retinoic acid isomer.



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  		Figure 3. Rate of all-trans-RA formation from 13-cis-RA ({bullet}) and 9-cis-RA ({circ}). 10 nM to 10 µM 13-cis-RA and 9-cis-RA were incubated in RPMI medium with 10% FCS. After 48 h, the incubations were stopped and medium was analyzed for retinoic acid isomers. The data represent mean values ± SD from three individual experiments.

Incubation experiments, carried out in cell-free RPMI 1640 medium after addition of NEM, confirmed that the observed isomerization was mediated by thiol groups ( Fig. 4A). Apart from the inhibition of oxidation, ascorbic acid also effectively inhibited isomerization of the retinoic acids used, indicating the ability of free radicals to promote this process ( Fig. 4B). The antioxidant melatonin, which preferably traps hydroxyl and peroxyl radicals, significantly reduced retinoic acid oxidation and thus provided clues for the peroxidation of retinoic acids in vitro ( Fig. 4C) (26, 27). Its limited effects on retinoic acid isomerization ruled out the participation of hydroxyl and peroxyl radicals in retinoic acid isomerization. Protein binding protected retinoic acids from oxidation and reduced their rate of isomerization. However, doubling the amount of FCS had no further effect on the stability of the retinoic acid isomers in vitro ( Fig. 4D, E).



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  		Figure 4. Modulation of retinoic acid isomerization and oxidation by proteins, NEM, and antioxidants. All-trans-RA (1 µM) was incubated in cell-free RPMI medium supplemented with 10% FCS in the presence of 100 µg/ml NEM (A), 2 mM ascorbic acid (B), and 5 mM melatonin (C). To analyze the influence of proteins, all-trans-RA (1 µM) was incubated with 10% FCS (D), with 20% FCS (E), and without serum (F). Each figure represents the mean values of three experiments. The experiments were repeated for 13-cis-RA and 9-cis-RA, and showed similar results with respect to the modulation of retinoic acid oxidation and isomerization.

Although HL-60 cells were cultivated in the presence of 10% FCS, which contained 454.1 ± 118.3 nM all-trans-retinol and <1.7 nM retinoic acids, no retinoic acids were detected in untreated HL-60 cells. When 13-cis-RA, 9-cis-RA, and all-trans-RA were added, they entered the cells immediately and reached maximal cellular concentrations within 48 h. Except for the 9,13-di-cis-isomer, all retinoic acid isomers generated in the medium were also detected in HL-60 cells ( Fig. 5). Peak concentrations of all-trans-RA in HL-60 cells (47.3±1.7 pmol/106 cells) were about fourfold higher than peak concentrations of 13-cis-RA (13.9±2.5 pmol/106 cells) and 9-cis-RA (13.5±2.3 pmol/106 cells) ( Fig. 6). 13-Cis-RA and 9-cis-RA, despite their structural difference, did not differ in their cellular uptake. When incubated with cis-isomers, the concentration of all-trans-RA increased in HL-60 cells, and all-trans-RA became the main retinoic acid isomer in the cells with peak concentrations of up to 18.9 ± 4.4 pmol/106 cells. Considering the higher rate of all-trans-RA formation from 13-cis-RA (0.066 pmol/min) compared to 9-cis-RA (0.045 pmol/min) (Figs. 2, 3) and its better uptake by HL-60 cells, the cellular all-trans-RA concentrations were in good correlation with the corresponding all-trans-RA concentrations in the medium (R>0.7, P<0.001, Pearson correlation). As no retinoic acids were detected in phosphate-buffered saline after the second washing and no 9,13-di-cis-RA was detected in the cells, contamination of the cellular extracts by medium was excluded.



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  		Figure 5. HPLC traces showing retinoic acid isomers in medium (A) and HL-60 cells (B) after 72 h incubation with 10 µM 13-cis-RA. Peaks are as follows: 1. 13-cis-RA, 2. 9,13-di-cis-RA, 3. 9-cis-RA, 4. all-trans-RA, I.S. internal standard acitretin. Separation was performed on two Nucleosil 100 (5 µm) columns connected in series with n-hexane, 1-heptanol (199:1, v/v) containing 10 mM trifluoroacetic acid at a flow rate of 1.5 ml/min.



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  		Figure 6. Cellular retinoic acid disposition in HL-60 cells during the incubation with 13-cis-RA (A), 9-cis-RA (B), and all-trans-RA (C). HL-60 cells (5x105 cells/ml) were incubated with 1 µM of 13-cis-RA, 9-cis-RA, and all-trans-RA in RPMI 1640 medium supplemented with 10% FCS and antibiotics. At specified times, cells were separated from medium by centrifugation (400 x g for 10 min at 4°C), washed twice with 20 ml of ice-cold buffered saline (pH 7.2), and counted on a hemocytometer. For quantification of retinoic acid isomers, about 5 to 10 x 106 cells were extracted. The data represent mean values ± SD from three individual experiments.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The natural retinoids are known for their susceptibility to isomerization, which requires careful handling and special laboratory precautions (28). Thus, to avoid the formation of retinoic acid isomers, which transactivate different receptor response pathways, there is agreement that protection from light is imperative in order to assess retinoic acid effects in vitro. However, apart from photoisomerization, single thiol compounds have been shown to catalyze the isomerization of 13-cis-RA, 9-cis-RA, and all-trans-RA (19–21). Due to the presence of thiol-containing compounds and the formation of biologically active retinoic acids by thiol-mediated isomerization, this process deserves special attention with respect to the interpretation of retinoic acid effects in vitro. The analysis of retinoic acid isomers incubated under cell culture conditions frequently used for the cultivation of HL-60 cells and other leukemic cell lines confirmed a profound, nonstereospecific isomerization for all isomers used. Regarding the retinoic acid isomers formed, the lack of saturation and the modulation by NEM, ascorbic acid, and melatonin, retinoic acid isomerization in the medium exhibited the same features reported for thiol radical-mediated isomerization. The proportional distribution of the retinoic acid isomers formed from all-trans-RA within 24 h in serum-containing medium was in good accordance with those results reported for incubations of all-trans-RA with liver microsomes (22). In vivo, the same four isomers were detected in plasma from humans and animals after the application of 9-cis-RA and all-trans-RA, supporting the hypothesis of thiol-mediated isomerization in the plasma compartment (29–31). In vivo isomerization, however, occurred to a much lesser extent (30, 32, 33).

The determination of cellular retinoic acid concentrations during incubation with 13-cis-RA, 9-cis-RA, and all-trans-RA demonstrates the importance of this nonstereospecific isomerization in medium. All-trans-RA reached significantly higher concentrations in HL-60 cells compared to 13-cis-RA and 9-cis-RA; this is consistent with observations in animals, where all-trans-RA reached higher tissue concentrations than 13-cis-RA (34, 35). Due to better cellular uptake, concentrations of all-trans-RA increased in cells while it formed in the medium, and all-trans-RA became the main cellular isomer in the cells during incubation with 13-cis-RA and 9-cis-RA. As nucleophilic thiol groups are ubiquitous in cells, thiol-mediated isomerization has been proposed as being relevant for cellular retinoic acid isomerization despite its lack of stereospecificity. However, the absence of the 9,13-di-cis isomer despite high cellular concentrations of 13-cis-RA, 9-cis-RA, and all-trans-RA contradicts the hypothesis of a nonstereospecific, thiol-mediated isomerization on the cellular level.

Although our studies focused on experimental settings used for cultivation of leukemic cells, they demonstrate in plain terms the proportions that retinoic acid isomerization might assume in vitro and give one reason for the inconsistent efficacy of single retinoic acid isomers in vitro and in vivo. Despite differentiation induction of promyelocytic blasts by 13-cis-RA in vitro, treatment of APL with this retinoic acid isomer seems to be less convincing in the light of the few published case reports (36–38). In addition, only one of seven patients who relapsed from acute promyelocytic leukemia reached complete remission with 9-cis-RA, although their leukemic blasts showed sensitivity for 9-cis-RA in vitro (39). Based on our observations, these and other inconsistent results might well be explained by different extents of retinoic acid isomerization in vivo and in vitro.

Furthermore, our observations point to the limited possibilities of overcoming chemically induced retinoic acid isomerization in vitro. Additive or synergistic effects will hamper or even prevent the correlation of cellular retinoic acid concentrations with retinoic acid effects in vitro. Because of its own pharmacological effects, the addition of ascorbic acid is of debatable value (40). So far, renewal of cell culture medium at least every 24 h, or more frequently, appears to be the most useful approach, though it will not overcome this problem either.

To develop new strategies for the use of retinoic acids in cancer treatment and to improve present treatment protocols, additional studies are needed in vivo and in vitro. However, due to the simple mechanism responsible for retinoic acid isomerization in vitro and its profound influence on cellular drug levels, in vitro data on the efficacy of single retinoic acid isomers require careful discussion and cautious interpretation, especially if these studies provide the basis for further clinical trials.


   ACKNOWLEDGMENTS
 
This work was supported by the Federal Department of Research and Technology (#01 EC 9401). The authors thank Mrs. G. Braun-Munzinger for editing the manuscript.


   FOOTNOTES
 
1 Correspondence: Centre of Pediatrics, Department of Hematology and Oncology, Westfälische Wilhelms-Universität Münster, Albert-Schweitzer Str. 33, D-48149 Münster, Germany. E-mail: boosj{at}uni-muenster.de.

2 Abbreviations: 13-cis-RA, 13-cis-retinoic acid; 9-cis-RA, 9-cis-retinoic acid; 9,13-di-cis-RA, 9,13-di-cis-retinoic acid, all-trans-RA, all-trans-retinoic acid; RAR, retinoic acid receptor; RXR, retinoid X receptor; HPLC, high-pressure liquid chromatography; FCS, fetal calf serum; NEM, N-ethylmaleimide; APL, acute promyelocytic leukemia.

Received for publication May 13, 1998. Revision received July 22, 1998.
   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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