Copper transporters regulate the cellular pharmacology and sensitivity to Pt drugs

Critical Reviews in Oncology/Hematology 53 (2005) 13–23

Copper transporters regulate the cellular pharmacology and sensitivity to Pt drugs Roohangiz Safaei∗ , Stephen B. Howell Department of Medicine and the Rebecca and John Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093-0058, USA Accepted 23 September 2004

Contents 1.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14

2.

Cu homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Cu influx transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Cu chaperones and buffering proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Cu efflux transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14 14 15 15

3.

Cross-resistance between Cu and the Pt drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Parallel alterations in the cellular pharmacology of Cu and the Pt drugs in Pt drug-resistant cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Expression of Cu transporters in Cu and Pt drug-resistant Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. CTR1 regulates cytotoxic sensitivity and Pt drug influx . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. ATP7B regulates cytotoxic sensitivity and Pt drug efflux . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. ATP7A regulates cytotoxic sensitivity and Pt drug accumulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

16 17 17 18 18 18

4.

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract Recent studies have demonstrated that the major Cu influx transporter CTR1 regulates tumor cell uptake of cisplatin (DDP), carboplatin (CBDCA) and oxaliplatin (L-OHP), and that the two Cu efflux transporters ATP7A and ATP7B regulate the efflux of these drugs. Evidence for the concept that these platinum (Pt) drugs enter cells and are distributed to various subcellular compartments via transporters that have evolved to manage Cu homeostasis includes the demonstration of: (1) bidirectional cross-resistance between cells selected for resistance to either the Pt drugs or Cu; (2) parallel changes in the transport of Pt and Cu drugs in resistant cells; (3) altered cytotoxic sensitivity and Pt drug accumulation in cells transfected with Cu transporters; and (4) altered expression of Cu transporters in Pt drug-resistant tumors. Appreciation of the role of the Cu transporters in the development of resistance to DDP, CBDCA, and L-OHP offers novel insights into strategies for preventing or reversing resistance to this very important family of anticancer drugs. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: ATP7A; ATP7B; Carboplatin; Cisplatin; Copper; hCTR1; Oxaliplatin

∗

Corresponding author. Tel.: +1 85 882 21117/9209 30058. E-mail address: [email protected] (R. Safaei).

1040-8428/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2004.09.007

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R. Safaei, S.B. Howell / Critical Reviews in Oncology/Hematology 53 (2005) 13–23

1. Introduction The major platinum (Pt) drugs currently used in the clinic include cisplatin (DDP), carboplatin (CBDCA) and oxaliplatin (L-OHP). DDP and CBDCA generally have a similar spectrum of clinical activity whereas L-OHP is distinguished by virtue of its activity in colon cancer. For any one of these drugs, some tumors are completely resistant and no clinical response is attained. More commonly, the initial cycles of chemotherapy produce some evidence of response, but for all three drugs resistance emerges during continued therapy. In cell line models, such acquired resistance to the Pt drugs is quite stable and the phenotype is co-dominant in somatic cell hybrids [1]. The mechanisms that account for this phenotype of acquired drug resistance have been the subject of intensive study, and it now appears that multiple pathways can contribute and that the primary mechanism may be different in different model systems (reviewed in [2]). Much attention has focused on the transport of the Pt drugs because, across a myriad of different cell line systems, decreased accumulation, which may be due to defects in uptake and/or efflux, is the single most commonly observed defect found in resistant cells. Over the past 4 years a series of studies have suggested that the mechanisms that evolved for the management of copper (Cu) homeostasis play an important role in the uptake and efflux of the Pt drugs, and can modulate sensitivity to the cytotoxic activity of these agents. This review outlines and summarizes the studies that link Cu homeostasis mechanisms to Pt drug resistance and provides a unifying hypothesis that can be tested in future studies.

2. Cu homeostasis Cu is an essential but toxic metal. Its ability to undergo reversible oxidation from Cu(I) to Cu(II) under physiologic conditions is central to critical cellular functions such as electron transport and the detoxification of reactive oxygen [3]. However, oxidation of Cu(I) produces reactive oxygen species, and thus Cu can be toxic to cells. The potential toxicity of Cu(I) is checked by a number of chaperones and buffering molecules that bind Cu(I) [4]. The central feature of the Cu homeostasis system is the presence of unique protein domains, rich in cysteine, methionine or histidine, called metal binding sequences (MBS). MBS bind Cu(I) in a protective pocket and hand it to the next protein through an intimate protein-protein interaction such that Cu is virtually never free in the cell. The concentration of free Cu in the cell has been reported to be <10−18 M [5]. Cu binds to chaperones and transporters through labile electrostatic associations, and is easily trans-chelated between MBS-containing molecules [6]. Cu homeostasis molecules are conserved in nature. Orthologs from mammalian cells can complement Cu transport deficits in yeast [7], and mutations that disable ATP7A and ATP7B proteins in Menkes and Wilson’s disease patients also

Fig. 1. Schematic depiction of copper distribution in a mammalian cell. Copper, taken up via hCTR1 is transferred to chaperones ATX1, CCS and COX17, which transfer it to ATP7A/ATP7B, Cu–Zn superoxide dismutase and cytochrome c oxidase respectively. Copper binding to ATP7A and ATP7B, induces subcellular trafficking of vesicles that contain the two proteins from the trans-Golgi network (TGN) to more peripheral locations. These proteins transfer Cu to cuproenzymes, such as tyrosinase and ceruloplasmin.

disable the ortholog protein CopB ATPase in Enterococcus hirae [8]. Fig. 1 presents a schematic drawing of the major Cu homeostasis pathways in mammalian cells. 2.1. Cu influx transporters The main Cu uptake transporter in human cells is hCTR1, a 190 amino acid protein with three transmembrane domains [9,10]. hCTR1 can form oligomeric complexes, possibly to facilitate pore formation for Cu uptake [11–13]. Two recent studies in transgenic mice have demonstrated that CTR1 is essential for the survival of mammalian embryos [12,14]. CTR1 resides predominantly in the plasma membrane [12,13] and its ability to transport Cu is temperature, pH, and K+ iondependent [15]. The methionine- and histidine-rich amino terminal of hCTR1 may be important in Cu binding. Fig. 2 shows a schematic drawing of the topology of hCTR1. In addition to CTR1, other Cu transporters also exist which, together with the divalent metal transporter 1 (DMT1; also known as natural resistance associated macrophage protein 2, or Nramp2) and divalent cation transporter 1 (DCT1), may account for some component of Cu uptake in mammalian and other eukaryotic cells [16]. Nramp2 is an integral membrane protein predicted to contain 12 transmembrane domains [17]. Direct transport studies in Xenopus laevis oocytes suggest that Nramp2 is a pH-dependent divalent metal transporter with broad substrate specificity that is capable of transporting Fe2+ , Mn2+ , Co2+ , Cd2+ , Cu2+ , Ni2+ , Pb2+ , and possibly Zn2+ and may function by a H+ co-transport mechanism [18]. It has also recently been reported to be capable of transporting Cu [16].

R. Safaei, S.B. Howell / Critical Reviews in Oncology/Hematology 53 (2005) 13–23

15

Fig. 2. Proposed topology of the human CTR1 protein. The methionine residues (M) at the extracellular amino-terminal domain are required for Cu binding.

2.2. Cu chaperones and buffering proteins As shown in Fig. 1, once inside the cell Cu is delivered from CTR1 to various chaperones by mechanisms that are not well characterized. These chaperones are pathway specific. ATX1 (HaH1) delivers Cu to the P-type ATPases ATP7A [19] and ATP7B [20] that concentrate it into the trans-Golgi network (TGN) whence it is delivered to Cu-requiring enzymes in the secretory pathway (for example, tyrosinase and ceruloplasmin [21,22]). COX17 is required for delivery of Cu to cytochrome-c oxidase in the mitochondria [23], and CCS is needed to load Cu onto cytoplasmic SOD1 [24]. 2.3. Cu efflux transporters Export of Cu from mammalian cells involves two P-type ATPases, ATP7A and ATP7B. Two human genetic diseases of Cu metabolism, Menkes and Wilson’s diseases are, respectively, caused by mutations in ATP7A and ATP7B. Impaired

cellular efflux of Cu is the main cause of excessive Cu accumulation in the liver, brain, and kidney of patients with Wilson’s disease and in the brain of those with Menkes disease. Experiments on animals that carry mutations in ATP7A (brindled mice) [25] and ATP7B (Long Evans Cinnamon rats [26,27] and toxic milk mice [28,29]), have confirmed the physiologic significance of these transporters. The two Cu efflux proteins, ATP7A and ATP7B, are homologous both in structure (54% amino acid similarity [30]) and in function. ATP7B is expressed in liver and kidney and to a lesser extent in brain of normal individuals, consistent with excessive Cu accumulation observed in these tissues when ATP7B function is lost in patients with Wilson’s disease [31]. ATP7A is expressed in the intestinal epithelium [32] as well as most other tissues other than liver, and the pathology of Menkes disease reflects inadequate mobilization of Cu from a number of tissues [33–35]. Fig. 3 presents a schematic drawing of the ATP7B and ATP7A molecules as-

Fig. 3. Schematic diagram of the transmembrane organization of Cu transporting ATPases ATP7A and ATP7B. The MBS sequences with CXXC motifs at the N-terminal end, the DKTG phosphorylation site, the TGDN ATP binding site, and the TGEA phosphatase domain are conserved in all of the P-type ATPases.

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R. Safaei, S.B. Howell / Critical Reviews in Oncology/Hematology 53 (2005) 13–23

sembled in the plasma membrane. Both proteins have eight membrane spanning domains [31,36,37] of which the sixth is conserved and forms the channel through which Cu moves (references in [38]). Both proteins also have 6 “metal binding sequences” (MBS) repeats of approximately 70 amino acids each at the N-terminal cytosolic side. Each MBS repeat has a core sequence of GMTCXXCIE [30,36,39] that is similar to motifs found in mercury binding proteins and the cadmium ATPase in bacteria [40–43]. ATP7B and ATP7A are P1 -(CPx)-type ATPases, and like other P-type ATPases, function as monomers (reviewed in [44]). They can be inhibited by vanadates, and form an intermediate acylphosphate through the transfer of a ␥-phosphate from ATP to an aspartic acid residue. As shown in Fig. 3, the signature motifs of these proteins include: a phosphatase domain, TGEA; the CPC (cysteine and proline) and SEHPL sequence; a DKTGT motif that contains an invariant aspartate residue; the TGDN sequence that binds ATP; and, a conserved “hinge” region that provides a flexible loop connecting the ATP-binding domain to the transmembrane portion of the molecule [30]. The major function of ATP7A and ATP7B is to couple the energy of ATP hydrolysis with the uphill transport of cations across cell membranes. An important feature of both ATP7B and ATP7A proteins is their ability to undergo constitutive and Cu-stimulated trafficking [45–47]. Cu triggers the movement from the transGolgi network (TGN) to more peripheral membrane compartments and, in the case of ATP7A, the plasma membrane [48–50]. Cu-induced trafficking of the vesicles containing ATP7A and ATP7B proteins appears to be highly regulated by intramolecular phosphorylation [51] and trafficking molecules such as rab5 and rab7 GTPases [52].

3. Cross-resistance between Cu and the Pt drugs One of the earliest hints that Cu homeostasis mechanisms might be involved in resistance to the Pt drugs was the observation that, while DDP, CBDCA, and L-OHP exhibit varying degrees of cross-resistance to each other [53,54], cells resistant to DDP are cross-resistant with other metal or metalloidcontaining agents [55–57]. Table 1 summarizes the data on a large number of different types of compounds. Evidence that the cross-resistance is bidirectional was provided by later studies. As shown in Table 2, analysis of survival and transport parameters in six cell lines, four of which were selected for resistance to Pt drugs and two for resistance to Cu, demonstrated that regardless of which drug the resistant cells were initially selected with, they all were crossresistant to Cu, CBDCA, DDP and arsenite [58,59]. The four Pt drug-resistant cell lines, consisting of the three human ovarian carcinoma sublines 2008/C13*5.25, A2780/CP and IGROV-1/CP and the head and neck carcinoma cell line UMSCC10B/15S, were all highly resistant to Pt drugs but exhibited low or moderate level resistance to Cu when compared to their respective parental lines 2008, A2780, IGROV-1 and UMSCC10B [58,60]. The same pattern was also observed in two Cu-resistant sublines, CuR23 and CuR27, which were selected by exposure of hepatocarcinoma HuH7 cells to Cu [61]. IC50 values obtained from clonogenic assays of cells exposed in parallel to DDP, CBDCA, and CuSO4 either continuously [60] or for 1 h [58] revealed that while cells were 2–20-fold resistant to Pt drugs they were only 2–4-fold resistant to Cu [58]. Cu and the Pt drugs are believed to cause cell death by different mechanisms. Excess Cu generates reactive oxygen

Table 1 Cross-resistance between Pt drugs, metals and metalloids Metal

Pt drug

Cell type

Phenotype

Reference

DDP, L-OHP

Human KCP-4, a resistant subline derived from KB-3-1 Human leukemia CCRF-CEM/CDDP Human ovarian cells A2780 and 2780/CP20 Cd-rA7 and Cd-rB5, metallothionein null Fibroblast

↑ NRE activity, ↑ efflux

[97]

Low level cross-resistance to gold

[98]

Various degrees of cross-resistance

[99]

↓ Drug accumulation

[100]

Human hepatoma and a cervical adenocarcinoma Human ovarian carcinoma A2780/CP70 Human ovarian 2008/C13*5.25

↓ Drug accumulation

[57]

↓ Drug accumulation, ↑ increased tolerance to higher levels of DNA damage ↓ Drug accumulation, ↑ glutathione, ↑ metallothioneins ↑ Glutathione, no change in drug accumulation, ↓ DNA adducts No change in metallothionein mRNA, high resistance to DDP, Low resistance to Cd ↓ Drug accumulation, no change in GSH levels No change in drug accumulation, ↑ GSH transferase (GST) activity

[101]

Au

DDP

Cd, Bi, Ca, K, Mg, V, Se, Cu, Zn, Fe Cd, Zn, Cu, Hg, Ni,

DDP DDP

As As, Sb, Cd

DDP

Cd

DDP

Cd, Zn, Sb

DDP

Cd

JM15, DDP

Cd

DDP

As, Sb, Cd, Ni

DDP

Cd

DDP, CBDCA

Human ovarian carcinoma 41M and CH1 Subline of human ovarian carcinoma A2780 Rat liver cells exposed to arsenite Human bladder cancer cells J82/MMC

↑ Efflux

[55] [102] [103] [104] [105]

[59,60] ↑

[60] ↑

↓ ↑ ↓ 1.5

↓ 1.2

↑ 8.9 CuR23

↓

– 8.6 CuR27

↑ 23 PC5

↓

–

↓ ↑

↓ ↑ ↓ 2.0 ↓ ↑ 7.5 IGROV-1/CP

↓

– ↓ – ↓

↑ – ↑

↑ ↑ 8.1 A2780/CP

↓

↓

2.1

↓

↑

↓

ATP7A hCTR1 ATP7A hCTR1 ATP7B hCTR1 ATP7B ↓ ↑ ↓ 1.5 ↓ ↑ 5.7 2008/C13*5.25

↓

ATP7B hCTR1 ATP7B hCTR1

[74] and references therein

[58]

[58]

[58] ↑

↓ – ↓ – – No change –

17

species that have the potential to damage many components of the cellular machinery, whereas the cytotoxic effect of Pt drugs is mediated largely through the formation of adducts in DNA. Thus, the demonstration of cross-resistance focused attention on the possible role of Cu transporters rather than more down-stream elements of the apoptotic pathway as most likely to account for overlapping phenotype of Cu and Pt drug-resistant cells. 3.1. Parallel alterations in the cellular pharmacology of Cu and the Pt drugs in Pt drug-resistant cells Reduced drug accumulation is a common and distinctive feature of cells with the acquired Pt drug-resistant phenotype [62–70]. Although the relationship between the degree of resistance to Pt drugs and the level of accumulation in cells is not always direct [71], 70–90% of the total resistance has been attributed to defective Pt drug accumulation in some cases [72]. Parallel changes in Cu and Pt transport were detected in several studies of accumulation and efflux. All of the six cross-resistant cell lines shown in Table 2 accumulated lower levels of Cu and the Pt drugs than their drug-sensitive parental lines when analyzed either after 1 min or 1 h of drug exposure. At 1 min, DDP accumulation in the resistant cells was 23–56% [59] of that in the control cell lines. The levels of Cu accumulation at 1 min in the resistant cells were 36–75% in the parental control [58,59]. At 1 h, the accumulation of DDP in the resistant cells was 38–67%, and that of Cu 27–58%, respectively, of that in the sensitive parental lines [58,59]. Cells resistant to Pt drugs also formed 10–38% fewer Pt–DNA adducts than their sensitive parental cells [58]. As shown in Table 2, resistant cells also effluxed Pt and Cu at a more rapid rate than the control parental cells. Two phases of efflux were detected: a rapid phase during which only a small fraction of the Cu and Pt present in the cell was exported, and a very much slower phase during which very little additional Cu or Pt was lost from the cells. Cu and Pt efflux during the initial phase was clearly increased in the resistant cells. The increase in the initial rates of efflux in resistant cells ranged from 2.3 to 2.5-fold for DDP, and 2.4 to 6.2-fold for Cu [58,59]. Study of efflux parameters demonstrated that the efflux of DDP was slower than that of Cu. An important observation in these studies was that, when grown in regular medium, all resistant cells had lower steadystate levels of Cu that ranged from 22–56% of those in sensitive cell lines. Perturbation of the basal Cu level is a sensitive indictor of alterations in Cu homeostasis mechanisms, and this observation suggests abnormalities of these mechanisms in both Cu and Pt drug-resistant cells [58,59].

DDP

3.2. Expression of Cu transporters in Cu and Pt drug-resistant Cells Cu

Reference Protein levels RNA levels Efflux rate Cu content Efflux rate Fold resistance

Pt content

Pt–DNA adduct

Fold resistance

Cu DDP Cell line Drug used for selection

Table 2 Cells selected for resistance to Cu or Pt drugs show parallel pharmacokinetic changes and transporter expression properties

Basal Cu content

Transporter

Cu transporter studied

R. Safaei, S.B. Howell / Critical Reviews in Oncology/Hematology 53 (2005) 13–23

Analyses of Cu and Pt drug-resistant cells by Western blotting and RT-PCR revealed that they expressed altered levels

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of one or more of the proteins involved in Cu homeostasis. For example, the levels of the Cu efflux protein ATP7B were, respectively, 2.3 and 3.9 times higher in Cu-selected hepatocellular carcinoma CuR23 and CuR27 sublines than in their sensitive parental HuH7 cells [59,73]. Similar results were also reported by Schilsky et al. [61]. The DDP-selected cross-resistant ovarian carcinoma sublines 2008/C13*5.25 and A2780/CP had higher levels of ATP7A than their sensitive parental lines, while the IGROV-1/CP DDP-resistant line had higher levels of ATP7B [58]. Western blot analysis of the Cu chaperone HaH1 demonstrated unchanged levels of this protein [58]. Komatsu et al. [74] reported that the DDP-resistant human prostate carcinoma cell line PC-5 exhibits increased levels of the ATP7B protein, while two other DDP-resistant human prostate carcinoma cell lines PC-3 and PC-5R did not. 3.3. CTR1 regulates cytotoxic sensitivity and Pt drug influx The role of Cu uptake protein CTR1 in mediating transport and sensitivity to the Pt drugs has been demonstrated in both yeast and mammalian cells [75,76]. Ishida et al. [75] observed that S. cerevisiae lacking the yCTR1 transporter were resistant to the cytotoxic effect of DDP and accumulated less drug. Lin et al. [76] confirmed and extended this observation to show that yCTR1 mediated the uptake of all three clinically used Pt drugs as well as several other DDP analogs. A study in mouse embryo fibroblasts lacking either one or both of the mCTR1 alleles demonstrated a progressive reduction in drug uptake and increase in drug resistance with loss of first one and then both mCTR1 alleles [75]. Involvement of human CTR1 in the regulation of Pt drug uptake and killing was further demonstrated by Holzer et al. [77] who showed that transfection of the human ovarian carcinoma cell line A2780 with an hCTR1 expression construct rendered these cells more sensitive to DDP. The increased sensitivity was associated with significantly higher accumulation levels of the drug. The Pt drugs and Cu inhibit each other’s uptake in a concentration-dependent manner [75,76], and both cause degradation of CTR1 in yeast cells [75]. Interestingly the factors that influence the uptake of the Pt drugs, such as dependence on temperature, pH [78–80], K+ ions [81] and reducing agents [82–84] also affect the uptake of Cu via the Cu transporter CTR1 in mammalian cells [85]. These results provide strong evidence that CTR1 regulates cellular uptake of the Pt drugs and is a major route of drug entry. How this is accomplished is not yet clear. One possibility is that the Pt drugs bind to CTR1 and are internalized by endocytosis [86]. CTR1 is rich in histidine and methionine residues for which DDP has high affinity [85]. Alternatively, the Pt drugs may cross the plasma membrane through a channel formed by three hCTR1 molecules [87].

3.4. ATP7B regulates cytotoxic sensitivity and Pt drug efflux As shown in Table 3, by transfecting an ATP7B expression construct into the epidermoid carcinoma K-B-3-1 cell line, Komatsu et al. [74] succeeded in enhancing resistance to DDP by 8.9-fold and to Cu by 2.0-fold. Studies by Katano et al. [88] extended these findings by demonstrating that transfection of head and neck and ovarian carcinoma cells with an ATP7B expression vector rendered them resistant to DDP, CBDCA and Cu. Transfection of a mouse cDNA into 2008 ovarian carcinoma cells was later shown to increase resistance in these cells not only to Cu but also to DDP, CBDCA and L-OHP [89]. Interestingly, ATP7B-transfected cells were found to have lower basal levels of Cu than empty vector-transfected cells [90]. ATP7B-transfected 2008 cells also accumulated significantly lower levels of Cu and CBDCA when measured after a 1 or 24 h incubation with 64 CuSO4 or 14 CBDCA. After a 5 min exposure to Cu or CBDCA, the ATP7B transfected cells accumulated 37 and 61%, respectively, of the Cu and Pt found in the control cell line. Increased expression of ATP7B protein in 2008 ovarian carcinoma cells not only reduced the whole cell and DNA content of Pt in DDP- and CBDCAtreated cells but also increased the rates of the primary and secondary phases of efflux for both of these Pt drugs [90]. The data published thus far provide strong evidence that ATP7B mediates resistance to the Pt drugs, and that it does so by regulating drug efflux. As shown in Table 4, immunohistochemical and mRNA analyses have demonstrated that, in many tumor types, higher expression of ATP7B correlates with unfavorable response to Pt drug treatment (for example, see [91,92]. No such correlation was found between the expression of other efflux drug transporters such as MRP1, MRP2, MDR1 and LPR and response to Pt drug therapy [91,92]. An association was also found between the level of ATP7B expression and presence of poorly or undifferentiated cells in tumors [91,92]. 3.5. ATP7A regulates cytotoxic sensitivity and Pt drug accumulation Substantially less information is available on the ability of ATP7A to modulate the cellular pharmacology of the Pt drugs. Study of the cellular pharmacology of Cu and DDP into the Me32a ATP7A-deficient human Menkes fibroblast cell line demonstrated that lack of ATP7A function was associated with increased accumulation of both Cu and DDP and hypersensitivity to both agents [89,93]. In another study human ovarian carcinoma 2008 cells were rendered more resistant to DDP when transfected with an ATP7A expression vector even when the magnitude of the increase in ATP7A above endogenous levels was quite small [93]. As for ATP7B, there is immunohistochemical evidence that the expression of ATP7A influences sensitivity to the Pt drugs as measured by clinical tumor response. An anal-

Table 3 Cells transfected to express Cu proteins display parallel pharmacokinetic properties with respect to Pt drugs and Cu Gene transfected

ATP7B

Cell line

K-B-3-1 2008

ATP7A

2008

Me32a

hCTR1

A2780

CuSO4

Reference

Fold resistance

Pt content

Efflux rate

Pt–DNA adduct

Fold resistance

Cu content

Efflux rate

Basal Cu content

8.9 DDP 2.6 DDP 2.6 CBDCA 1.6 DDP 1.7 DDP 1.5 CBDCA DDP 2.1 CBDCA >25 L-OHP 0.3

↓ DDP ↓ CBDCA

↑ DDP ↑ CBDCA

– ↓CBDCA

2 1.2

– ↓

– ↑

– ↓

[74] [90]

– – ↑ DDP ↑ CBDCA ↑ L-OHP

– –

– –

1.4 1.2 10.4

– – ↓

– – –

↓ – ↓

[90] [90] [89]

DDP 2 CBDCA 5 L-OHP 1.6 DDP 1.4 CBDCA 7.5 L-OHP 0.3

↑ DDP ↑ CBDCA ↑ L-OHP ↑ DDP ↑ CBDCA ↑ L-OHP

–

No change for DDP CBDCA or L-OHP

None

↓

↑

↓

[106]

–

↓ L-OHP

7.8

↓

↑

↓

[107]

↓ (Not significant)

↑ DDP

–

–

↓ (Not significant)

↑

–

–

[77]

↑L-OHP

Table 4 Correlation between drug resistance in human tumors and expression of gene products for copper transporters ATP7A and ATP7B Tumor type

Cu protein

Detection method

Prior Pt drug treatment

Outcome

Reference

Breast carcinoma

ATP7B

IHCa , RT-PCR

DDP

[91]

Ovarian carcinoma

ATP7B

RT-PCR

DDP

Esophageal carcinoma

ATP7B

IHCa

DDP

Oral squamous carcinoma

ATP7B

IHCa

DDP

Gastric carcinoma

ATP7B

IHCa

DDP

Prostate, breast, testes, kidney, pancreas, liver, thyroid, ovary, lung, endometrial, colon and other tumors

ATP7A

IHCa

Pt based

22% of samples were positive for ATP7B expression ATP7B expression was significantly higher in undifferentiated cells. No correlation between the outcome of therapy and the expression of MDR1, MRP1, LRP and BCRP was found 43.9% of samples were positive for ATP7B expression ATP7B expression was significantly higher in undifferentiated cells. No correlation between the outcome of therapy and the expression of MDR1, MRP1, LRP and BCRP was found 70.5% of samples were positive for ATP7B expression ATP7B expression correlated with unfavorable outcome of therapy ATP7B expression significantly correlated with unfavorable outcome of therapy 41.2% of samples were positive for ATP7B expression. ATP7B expression was significantly higher in undifferentiated cells All except liver and endometrial tumors expressed higher levels of ATP7A compared to normal tissue. Up regulation of ATP7A expression correlated negatively with survival

a

[108] [109] [110] [93]

19

Immunohistochemistry.

[92]

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IGROV-1 UMSCC10B Me32a

Pt drugs

20

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ysis of the expression of ATP7A in 54 patients with ovarian carcinoma before and after treatment with a Pt drugcontaining regimen demonstrated that, in some patients, treatment caused enrichment of the tumor for ATP7A-expressing cells, and the treatment outcome in patients in whom this occurred was quite poor [93].

4. Conclusion Evidence that Cu homeostasis proteins regulate sensitivity to Pt containing drugs and control their accumulation levels is now very strong. Exactly how CTR1, ATP7A, and ATP7B accomplish this, and what species of these drugs is involved, is less clear. The currently available data is consistent with the concept, outlined schematically in Fig. 4, that the Pt drugs are taken up, distributed into various intracellular compartments and exported from tumor cells by the system of transporters and chaperones that evolved to manage Cu homeostasis. In this model, the Pt drugs are envisioned as mimicking Cu in being transported into the cell via hCTR1 and being handed one of several chaperone molecules for delivery to transporters that then carry them into various subcellular compartments. Although consistent with the currently available data, there remain a large number of perplexing questions about the role of the Cu transporters in the influx and efflux of the Pt drugs. For example, the Cu transporters are highly selective for Cu as opposed to other metal ions, and for Cu(I) rather

than Cu(II), yet they seem promiscuous with respect to the Pt drugs. These transporters control the rate of influx and efflux of Pt drugs whose structures are markedly different from that of the Cu(I) ion. The fact that their expression modulates sensitivity to all three Pt drugs despite the differences in their structures is also remarkable. It is important to note that none of the Cu transporters has yet been formally shown to transport a Pt drug across a lipid bilayer membrane. Thus, it remains possible that the Cu transporters modulate intracellular levels of Pt drugs indirectly by regulating Cu-dependent activities such as ATP production, or simply by acting as a Pt drug trap. Secondary regulatory effects on Pt drug transport have been reported for other transporters such as the Na–KATPase [81], the Mg-ATPase [94], the Ca-ATPase [95], and the vacuolar ATPase [96]. As the two efflux transporters of Cu are known to function as monomers [42], it should be possible to address this issue using vesicles from cells engineered to express high levels of these proteins, or by assembling recombinant proteins in artificial membranes. While there may be other transporters that mediate influx or efflux of the Pt drugs and whose alteration can contribute to the acquired DDP resistant phenotype, it seems likely that a careful dissection of the mechanism by which the Cu transporters modulate sensitivity to the cytotoxic effects of these drugs will provide novel insights into how to prevent the emergence of resistance, or overcome it once it becomes apparent. Substantial work remains to understand Pt drug influx and efflux and to map the subcellular pathways by which these drugs move through cells, but insight into the involvement of the Cu transporters provides a starting point for the application of the powerful imaging and cell biological tools now available. Reviewers Prof. Franco Muggia, New York Medical Center, Kaplan Comprehensive Cancer Center (NCI Designated), 550 First Avenue, New York, NY 10016-6481, USA. Prof. Dr. Godefridus J. Peters, Head Clinical Research Laboratory Oncology, Department of Medical Oncology, VU University Medical Center, P.O. Box 7057, NL-1007 MB Amsterdam, The Netherlands. Marie H. Hanigan, Ph.D., Associate Professor of Cell Biology, University of Oklahoma Health Sciences Center, Biomedical Research Center, Room 264 975 N.E. 10th Street, Oklahoma City, Oklahoma 73104, USA.

Acknowledgements Fig. 4. A schematic model depicting the uptake, intracellular distribution and efflux of the Pt drug, DDP via Cu homeostasis molecules. DDP is taken up via hCTR1, loaded onto the copper chaperones ATX1, CCS and COX17 for transfer to ATP7A/ATP7B, cytosol and mitochondria. DDP binding to ATP7A and ATP7B induces structural changes that lead to the vesicular sequestration of the drug and trafficking of the ATP7A and ATP7B containing vesicles from the TGN to peripheral sites for eventual drug efflux.

We thank Wiltrud Naerdemann and Claudette Zacharia for technical and managerial assistance. Supported by grants CA95298 from the National Institute of Health and DAMD17-03-0158 from the Department of Defense, this work was conducted in part by the Clayton Foundation for

R. Safaei, S.B. Howell / Critical Reviews in Oncology/Hematology 53 (2005) 13–23

Research—California Division. Drs. Howell and Safaei are Clayton Foundation Investigators.

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Biographies Roohangiz Safaei, Ph.D. is a Scientist at the Rebecca and John Moores Cancer Center, University of California, San Diego and a Clayton Foundation Investigator. Address: Department of Medicine and the Rebecca and John Moores Cancer Center, University of California, San Diego, La Jolla, CA, 92093-0058 Stephen B. Howell, M.D. is Professor of Medicine at the University of California, San Diego and Clayton Foundation Investigator.