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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY
Division of Neoplastic Diseases, Department of Medicine (C.R.C., D.P.P., M.Y., J.P.W.) and Department of Pediatrics (J.W.), Medical College of Wisconsin, Milwaukee, Wisconsin
Received for publication
May 29, 2007
Accepted
June 27, 2007.
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Abstract |
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). Hence, there remains a great need to develop novel agents for the treatment of this malignancy. In the late 1970s, the group IIIa metal salt gallium nitrate was discovered to have antitumor activity in animal tumor models, and in subsequent clinical trials, it proved to have significant antineoplastic activity against non-Hodgkin's lymphoma and urothelial malignancies (Warrell et al., 1983; Weick et al., 1983; Keller et al., 1986; Chitambar et al., 1997; Einhorn, 2003; Chitambar, 2004). A more recent clinical trial confirmed the efficacy of gallium nitrate in patients with non-Hodgkin's lymphoma whose disease had relapsed following treatment with conventional chemotherapeutic agents (Pro et al., 2004).
The mechanisms responsible for the cytotoxicity of gallium are only partly understood. In the circulation, gallium binds to the iron transport protein transferrin (Tf) and may be incorporated into cells via Tf receptors (TfRs) present on the cell surface (Larson et al., 1980; Rasey et al., 1982; Harris and Pecoraro, 1983; Chitambar and Seligman, 1986; Chitambar and Zivkovic, 1987); Tf-independent pathways may also contribute to the uptake of gallium by certain cells (Chitambar and Zivkovic, 1987). Although much remains to be learned about the intracellular trafficking pathways for gallium, it is known that the steps leading to the inhibition of cellular proliferation by gallium involve a disruption of iron homeostasis and a diminution in the activity of iron-dependent ribonucleotide reductase (Chitambar and Seligman, 1986; Chitambar et al., 1988, 1991). More recently, it was shown that gallium nitrate induces apoptosis through a pathway that includes the activation of proapoptotic Bax, release of cytochrome c from the mitochondrion and downstream activation of effector caspases (Chitambar et al., 2006). Gallium may also act on other cellular process; however, the extent to which those actions contribute to its cytotoxicity remains to be determined (Collery et al., 2002).
Although gallium nitrate is a clinically active drug in lymphomas, a number of patients fail to respond to treatment, suggesting that their malignant cells have developed resistance to this drug. Tumor resistance to chemotherapy, whether to gallium nitrate or any other antineoplastic drug, is a major challenge to the successful treatment of malignancy. There is only a partial understanding of how cells manage to evade gallium's cytotoxicity. Using CCRF-CEM lymphoma cell lines made resistant to gallium nitrate, we have previously shown that these cells display a decrease in their uptake and intracellular accumulation of gallium and iron (Chitambar and Wereley, 1997, 1998). More recently, we reported that these gallium-resistant cells display a marked increase in the expression of metallothionein-2A, a low-molecular weight metal binding protein, and ZnT-1, a cell membrane-based protein involved in the efflux of zinc (Yang et al., 2007). The specific mechanisms by which these proteins modulate cell sensitivity to gallium are under investigation; however, current evidence suggests that the development of tumor cell resistance to gallium nitrate includes changes in gallium transport into cells as well as processes involved in intracellular metal sequestration.
The ability of gallium nitrate, a simple metal salt, to inhibit tumor cell growth in vitro and in vivo provides a strong rationale for continued research into the development of new gallium compounds with improved therapeutic application. One new candidate compound of interest is gallium maltolate, which consists of gallium bound to maltol (3-hydroxy-2-methyl-4-pyrone) and whose chemical structure has been previously reported (Bernstein et al., 2000). This gallium compound was recently shown be cytotoxic in hepatocellular carcinoma cell lines (Chua et al., 2006). The hydroxypyrones are a family of chelators with high affinity for a range of metal ions (Thompson et al., 2006). An important property of these chelators is that they are capable of not only mobilizing metal ions from cells but also delivering metals to cells. In the present study, we show that gallium maltolate is a more efficient inducer of apoptosis than gallium nitrate; its cytotoxicity is independent of p53 and extends to cells resistant to the growth-inhibitory effects of gallium nitrate. Induction of apoptosis by gallium maltolate is mediated through the mitochondria and includes an increase in the generation of reactive oxygen species. Our studies show that cellular gallium uptake is more efficient with gallium maltolate than with gallium nitrate and suggest that strategies to enhance the incorporation of gallium into cells may be an important approach to circumventing gallium resistance.
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Materials and Methods |
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Cell Lines. Gallium-sensitive CCRF-CEM cells were obtained from American Type Culture Collection (Manassas, VA). Galliumresistant cells were developed from this cell line by incubation of cells with incremental concentrations of gallium nitrate for several months, as described previously (Chitambar and Wereley, 1997). Lymphoid leukemic cell lines WTK1 (containing mutant p53, methionine to isoleucine substitution at codon 237 of the p53 gene) and TK6 (containing wt p53) and NH32 cells (p53 null) were provided by Dr. Lyuba Varticoski (National Cancer Institute, Bethesda, MD) and have been described previously (Little et al., 1995; Xia et al., 1995). Mantle cell lymphoma cell lines HBL-2, Granta, JVM-2, NCEB-1, and Z138C were obtained from the British Columbia Cancer Agency (Vancouver, Canada) and have been described previously (Tucker et al., 2006). All cells were grown in an atmosphere of 5% CO2 in RPMI 1640 supplemented with 10% bovine serum.
Cell Proliferation. The effects of gallium nitrate or gallium maltolate on cell proliferation were assessed by MTT assay as described previously (Mosmann, 1983). Cells (2 x 105/ml) were plated in 96-well microwell plates (100 µl/well) in the presence of increasing concentrations of either gallium compound. After 24 to 72 h of incubation at 37°C, 10 µl of MTT (5 mg/ml stock) was added to each well, and the incubation continued for an additional 4 h. One hundred microliters of 0.04 N HCl in isopropyl alcohol was then added to each well to solubilize the cells, and the absorbance of each well was determined by spectrophotometry at dual wavelengths of 570 and 630 nm using an EL808 microplate autoreader (Biotech Instruments, Winooski, VT). The absorbance of the wells containing additives was compared with wells in which the additives were omitted (control cells).
Caspase-3 Assay. Cells incubated with increasing concentrations of gallium maltolate or gallium nitrate for various periods of time were analyzed for caspase-3 activity using an Apo-One Homogeneous Caspase-3/7 assay (Promega, Madison, WI), which is based on the enzymatic cleavage of the fluorogenic caspase-3 substrate rhodamine 110, bis-(N-CBZ-L-aspartyl-L-glutamyl-L-valyl-L-aspartic acid amide. In selected incubations, the pan-caspase inhibitor z-VAD-fmk (R&D Systems, Minneapolis, MN) or the anti-TfR MoAb 42/6 was added to the incubation 1 h before the addition of gallium compounds. After incubation with gallium compounds, cells were counted, and equal numbers of cells were transferred to microwell plates (20,000 cells/well) for assay. The fluorescence from each well was measured by fluorometer using an excitation wavelength of 485 nm and emission wavelength of 530 nm. The fluorescence from cells treated with gallium compounds was expressed relative to that of cells not exposed to gallium.
Annexin V Staining. After 12 to 24 h of incubation with various concentrations of gallium maltolate, cells were washed with PBS, stained with annexin V FITC, and propidium iodide for 10 min, and analyzed by flow cytometry as recommended by the manufacturer.
Mitochondrial Membrane Potential. The effect of gallium maltolate on mitochondrial permeability transition was examined using JC-1 dye. Cells that had been incubated with increasing concentrations of gallium maltolate were washed, stained with JC-1 reagent, and then analyzed by two parameter flow cytometry, according to the manufacturer's recommendation.
Measurement of Reactive Oxygen Species in Cells. Intracellular reactive oxygen species (ROS) was measured as described previously (Said Ahmed et al., 2000). CCRF-CEM cells were plated (106 cells/ml) in 25-cm2 tissue culture flasks and loaded with 10 µM 6-carboxy-DCF-AM by incubation with this compound for 1 h. In selected flasks, 10 µM of the mitochondria-targeted antioxidant mito-Q was added, and the incubation continued for an additional hour. Gallium maltolate (0, 50, or 200 µM) was then added to each flask and after 2 or 3 h of incubation, 1 ml of cell suspension (106 cells) was removed and centrifuged. Cell pellets were resuspended in 400 µl of PBS and transferred to 96-well assay plates for fluorometry analysis. 2',7'-Dichlorofluorescein (DCF) fluorescence in each well was measured using an excitation wavelength of 495 nm and emission wavelength of 525 nm in a PerkinElmer 96-well plate reader (PerkinElmer Life and Analytical Sciences, Boston, MA).
Gallium Uptake. Gallium nitrate-sensitive and -resistant CCRFCEM cells were plated (5 x 105 cells/ml) in 1-ml multiwell plates and incubated with increasing concentrations of either gallium nitrate or gallium maltolate containing Ga-67 as a tracer (1 µCi of Ga-67/1 mM gallium nitrate or gallium maltolate). After 24 h of incubation, the number of cells in each well was counted with a hemocytometer, and the cells were harvested and washed with PBS by centrifugation. Ga-67 radioactivity in the cell pellet was counted in a gamma counter, and the amount of Ga-67 incorporated per 106 cells was determined.
Tf Binding Studies. CCRF-CEM cells were harvested, washed with ice-cold PBS containing 0.1% bovine serum albumin, and assayed for Tf binding at 37°C in the presence or absence of anti-TfR MoAb 42/6 using a previously described 125I-Tf binding assay (Chitambar and Seligman, 1986).
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Results |
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Gallium Maltolate Activates Caspase-3. To examine whether the cytotoxicity of gallium maltolate was the result of caspase activation, effector caspase-3 activity was measured in CCRF-CEM cells exposed to gallium compounds for various times. As shown in Fig. 1B, a concentration-dependent increase in caspase-3 activity was noted in cells incubated with gallium maltolate for 12 h. This activity was inhibited by the pancaspase inhibitor z-VAD-fmk, thus confirming that caspase-3 was indeed being activated (Fig. 1B). In contrast to gallium maltolate, gallium nitrate at similar concentrations did not produce a significant increase in caspase-3 activity after 12 and 24 h of incubation with cells. These results are consistent with the findings of the MTT assay (Fig. 1A) in which an inhibition of cell proliferation was not seen during the first 24-h incubation of cells with gallium nitrate. After 48 h, however, cells incubated with gallium nitrate displayed a concentration-dependent increase in caspase-3 activity (Fig. 1B). In additional experiments, caspase-3 activity was measured in cells incubated with 0 to 200 µM gallium maltolate for 3 and 6 h. Although an increase in caspase-3 activity was not detected at 3 h, a 2- and 4-fold increase in caspase-3 activity was seen after 6 h of incubation with 100 and 200 µM gallium maltolate, respectively (not shown). Hence, gallium maltolate inhibits cell growth and activates caspase-3 at earlier time-points and at lower concentrations than gallium nitrate.
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The signaling of cell death through the mitochondrion involves an increase in mitochondrial permeability transition that results in the release of cytochrome c and downstream activation of effector caspases (Zimmermann et al., 2001; Green and Kroemer, 2004). The increase in mitochondrial permeability transition is accompanied by a collapse in mitochondrial membrane potential that can be measured by JC-1 dye staining. In healthy nonapoptotic cells, JC-1 is taken up by mitochondria to produce a red fluorescence; however, with the loss of mitochondrial membrane potential, the dye remains in the cytoplasm to produce a green fluorescence. As shown in Fig. 2B, a progressive increase in green fluorescence and a loss of red fluorescence were noted in cells incubated with increasing concentrations of gallium maltolate for 12 h. The gallium-induced loss of mitochondrial membrane potential was even greater with longer incubation. After 24 h of incubation with 200 µM gallium maltolate, the population of cells with red fluorescence decreased from 92 to 51%, whereas the population of cells with green fluorescence increased from 4 to 46% (Fig. 2C).
Gallium Maltolate Increases Mitochondrial ROS Production. To examine whether the cytotoxicity of gallium maltolate was associated with oxidative stress, studies were conducted using 6-carboxy-DCF-AM, a nonfluorescent compound that can be incorporated into cells and oxidized to yield a detectable fluorescent product DCF. As shown in Fig. 3, in the absence of gallium maltolate, CCRF-CEM cells displayed a basal level of intracellular DCF fluorescence indicating the existence of endogenously generated ROS in these cells. This fluorescence increased significantly with exposure of cells to gallium maltolate and was consistent with a gallium-induced increase in intracellular ROS. As shown in Fig. 3, in the presence of 200 µM gallium maltolate, a significant increase in intracellular ROS above baseline was noted after 2 h of incubation. In contrast, in the presence of 50 µM gallium maltolate, an increase in intracellular ROS was seen after 3 h of incubation. To examine whether this ROS originated from the mitochondria, cells were incubated with the mitochondria-targeted antioxidant mito-Q before exposure to gallium maltolate. This approach has been used by other investigators to study mitochondria-generated ROS (Kelso et al., 2001; Dhanasekaran et al., 2004). As shown in Fig. 3, mito-Q completely blocked the gallium-induced increase in intracellular ROS. Interestingly, mito-Q produced a decrease in DCF fluorescence to a level below that seen in cells incubated with gallium maltolate alone, suggesting that this antioxidant blocked both gallium-induced and basal ROS production by the mitochondrion.
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; Rasey et al., 1982; Harris and Pecoraro, 1983; Chitambar and Seligman, 1986; Chitambar and Zivkovic, 1987); however, the relevance of this pathway to gallium maltolate-induced apoptosis is not known. To examine this, experiments were conducted to determine whether blockade of cell surface TfR function with MoAb 42/6 would affect the activation of caspase-3 by gallium maltolate. Binding studies were first conducted to confirm that 42/6 did indeed interfere with the interaction of Tf with its receptor. As shown in Fig. 4A, specific 125I-Tf binding to cells was markedly reduced by MoAb 42/6, consistent with previous reports that show that this MoAb blocks TfR function (Trowbridge and Lopez, 1982; Taetle et al., 1986). The next set of experiments examined whether TfR blockade by MoAb 42/6 affected gallium maltolate-induced apoptosis. As shown in Fig. 4B, 30 µg/ml MoAb 42/6 (a concentration sufficient to saturate cell surface TfRs) reduced gallium maltolate-induced caspase-3 activity; however, a significant level of caspase-3 activity still remained. This residual caspase-3 activity was due to gallium maltolate and not TfR blockade because 30 µg/ml MoAb 42/6 alone did not induce caspase-3 activity over a 24-h incubation (data not shown). Although MoAb 42/6 reduced caspase-3 activity, it had only a small effect on preventing cell growth inhibition by gallium maltolate. As shown in Fig. 4C, MoAb 42/6 reduced the growthinhibitory effect of 100 µM gallium maltolate by approximately 15% (p = 0.01 by Student's t test) but had no impact on cell growth inhibition by higher concentrations of gallium maltolate.
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Gallium Maltolate Cytotoxicity Is Independent of p53 Status. The role of p53 in gallium-induced apoptosis is not known. To examine this, lymphoma cell lines TK-6 (wildtype p53), NH-32 (p53 null), and WTK-1 (mutant p53) were examined for their sensitivity to growth inhibition by gallium compounds. As shown in Fig. 5, all three cell lines were sensitive to gallium maltolate. TK-6 and NH-32 cells were also sensitive to gallium nitrate, albeit to a lesser extent than gallium maltolate. The IC50 for gallium maltolate was 18 and 40 µM for TK-6 and NH-32 cells, respectively, whereas the IC50 for gallium nitrate was 145 and 150 µM for the same cell lines (Fig. 5). WTK-1 cells were markedly less sensitive to gallium nitrate; 450 µM gallium nitrate inhibited the growth of these cells by approximately 25% (Fig. 5). In contrast, WTK-1 cells were highly sensitive to gallium maltolate (IC50, 45 µM; Fig. 5). Hence, the growth of these p53 variant cell lines was inhibited uniformly by gallium maltolate but not by gallium nitrate.
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). As shown in Fig. 6A, gallium nitrate inhibited the proliferation of gallium-sensitive CCRF-CEM cells, whereas it failed to inhibit the growth of GnR cells. In contrast, the proliferation of GnR cells could be inhibited by increasing concentrations of gallium maltolate (Fig. 6, B and C). However, even though GnR cells were sensitive to gallium maltolate, their growth was not inhibited to the same extent as gallium-sensitive CCRF-CEM cells; the IC50 of gallium maltolate was 25 and 72 µM for gallium-sensitive and GnR cells, respectively (Fig. 6B). Consistent with the differential effects of these gallium compounds on GnR cell growth, gallium maltolate produced an increase in caspase-3 activity, whereas gallium nitrate failed to do so (Fig. 6D).
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Discussion |
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; Chitambar et al., 1996). In the present investigation, we report on a novel compound, gallium maltolate, and show that it displays significantly greater cytotoxicity than gallium nitrate, and, most importantly, it induces apoptosis in cells that are resistant to gallium nitrate. Compared with gallium nitrate, gallium maltolate-induced apoptosis occurs not only at lower gallium concentrations but also at significantly earlier incubation time-points. As demonstrated in this study and in previous investigations (Chitambar et al., 2006), the triggering of apoptosis by gallium nitrate in gallium-sensitive CCRF-CEM cells occurs after 24 to 30 h of incubation. In contrast, gallium maltolate induces apoptosis after 6 h of incubation.
Although gallium maltolate induces apoptosis more efficiently than gallium nitrate, both gallium compounds appear to eventually activate effector caspase-3 through a similar apoptotic pathway. Recently, we showed that gallium nitrate activates proapoptotic Bax, leading to the mitochondrial release of cytochrome c, downstream activation of caspase-3, and apoptosis (Chitambar et al., 2006). In the present study, using JC-1 dye, we show that the exposure of cells to gallium maltolate results in a loss of the mitochondrial membrane potential and an increase in mitochondrial permeability transition. These changes are known to herald the release of cytochrome c from the mitochondria and are consistent with the involvement of the mitochondrial pathway in apoptosis induced by gallium maltolate.
Having demonstrated an action of gallium maltolate on mitochondria, we examined whether its cytotoxicity was associated with the generation of intracellular ROS. These experiments revealed two important novel findings. First, an increase in intracellular ROS occurred as an early event (within 2 h) following the incubation of cells with gallium maltolate and preceded caspase-3 activation. Second, this increase in gallium-induced ROS production was completely blocked by the mitochondria-targeted antioxidant mito-Q, suggesting that ROS generated in the presence of gallium maltolate originated from the mitochondrion. Not surprisingly, even in the absence of gallium maltolate, CCRF-CEM cells had a basal level of endogenous ROS, a finding that is consistent with other reports that a small amount of ROS is physiologically present in cells as a byproduct of mitochondrial metabolism (Raha and Robinson, 2000). The source of this ROS appears to be complexes I and III of the mitochondrial electron transport chain that produce superoxide, which is dismutated to form hydrogen peroxide. The latter may, via the Fenton reaction, lead to the formation of the highly damaging hydroxyl radical (Lubec, 1996). How gallium maltolate increases ROS production is not clear. Although gallium does share certain properties with iron, it is not redox active; therefore, its ability to generate ROS may result from a direct action on steps in mitochondrial oxidative phosphorylation or the displacement of iron from intracellular proteins, thereby making iron available to catalyze ROS production. These potential mechanisms are currently being investigated.
For gallium to induce apoptosis, it must first be incorporated into cells. Prior studies have shown a role for Tf and the TfR in gallium uptake (Larson et al., 1980; Harris and Pecoraro, 1983; Chitambar and Zivkovic, 1987); however, cellular gallium uptake may also occur by a Tf-independent pathway (Chitambar and Zivkovic, 1987). Hence, to determine which uptake pathway is relevant to the mechanism of action of gallium maltolate, we examined the effects of gallium maltolate under conditions of TfR blockade. It should be noted that a limitation to the use of MoAb 42/6 for such studies is that TfR blockade may itself inhibit cellular iron uptake and reduce cell proliferation (Trowbridge and Lopez, 1982; Taetle et al., 1986). We therefore considered these independent effects of MoAb 42/6 and noted that the concentration of this antibody used in our experiments did not significantly activate caspase-3 or inhibit cell proliferation over a 24-h incubation. Our studies showed that although MoAb 42/6 blocked TfR function and reduced the level of caspase-3 activity induced by gallium maltolate, it did not abrogate caspase-3 activity, nor did it reverse the growth-inhibitory effects of gallium maltolate. Interestingly, MoAb 42/6 did provide partial protection (
15%) against growth inhibition by lower concentrations of gallium maltolate, suggesting that when gallium concentrations are limited, TfR-mediated gallium uptake (as Tf-Ga) does contribute gallium maltolate's cytotoxicity. In the latter situation, it is likely that Tf-Ga is formed by a transfer of Ga from maltol to Tf present in the culture medium. Overall, however, we conclude that although caspase-3 activation by gallium maltolate may result from gallium uptake by TfR-dependent and -independent pathways, the amount of caspase-3 activation by the latter pathway is sufficient to inhibit cell proliferation. Thus, the growth-inhibitory effects of gallium maltolate cannot be reversed by blocking TfR function. Gallium maltolate appears, therefore, to exert its apoptotic action by bypassing the TfR and delivering gallium to intracellular targets.
An important finding in our studies was that cells resistant to growth inhibition by gallium nitrate, including WTK-1 p53 mutant cells, were sensitive to gallium maltolate. Gallium maltolate inhibited cell growth and activated caspase-3 in gallium nitrate-resistant cells, whereas gallium nitrate failed to do so. Prior studies examining the mechanisms of tumor cell resistance to gallium nitrate have suggested that the development of such resistance includes a decrease in TfR-mediated gallium uptake and changes in the intracellular trafficking of gallium and iron (Chitambar and Wereley, 1997; Davies et al., 2006). The cytotoxicity of gallium maltolate in gallium nitrate-resistant cells may, therefore, be due, at least in part, to the ability of this compound to circumvent the TfR pathway and transport greater amounts of gallium into cells. Indeed, our studies demonstrating that cellular radiogallium uptake is greater with gallium maltolate than with gallium nitrate support this conclusion.
The development of metal-based drugs as therapeutic agents for cancer treatment is an important area for research. Recent studies have shown that metal complexes of tridentate chelators display antiproliferative activity against malignant cells in vitro (Bernhardt et al., 2006). The ability of gallium maltolate to induce apoptosis more efficiently than gallium nitrate and its activity against cells resistant to gallium nitrate makes it an attractive agent for further investigation. Gallium maltolate is presently in development in phase I clinical trials; studies are in progress to understand its mechanisms of action and to identify intracellular targets and molecular markers in lymphomas and other malignancies that may be of value in predicting tumor sensitivity to this compound.
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: Tf, transferrin; TfR, transferrin receptor; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium; FITC, fluorescein isothiocyanate; PI, propidium iodide; MoAb, monoclonal antibody; mito-Q, mitoquinone; ROS, reactive oxygen species; DCF, 2',7'-dichlorofluorescein; z, benzyloxycarbonyl; fmk, fluoromethyl ketone; 6-carboxy-DCF-AM, 6-carboxy-2',7'-dichlorodihydrofluorescein diacetate, di-acetoxymethyl ester.
Address correspondence to: Dr. Christopher R. Chitambar, Division of Neoplastic Diseases, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226. E-mail: chitambr{at}mcw.edu
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