Minireviews Open Access
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. Feb 10, 2016; 7(1): 106-113
Published online Feb 10, 2016. doi: 10.5306/wjco.v7.i1.106
Role of copper transporters in platinum resistance
Deepak Kilari, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, United States
Elizabeth Guancial, Eric S Kim, Departments of Medicine, University of Rochester Medical Center, Rochester, NY 14642, United States
Author contributions: All the authors contributed equally in writing the manuscript.
Conflict-of-interest statement: Authors declare no conflict of interests for this article.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Eric S Kim, MD, Department of Medicine, University of Rochester Medical Center, 601 Elmwood Ave, Rochester, NY 14642, United States.
Telephone: +1-585-2734150 Fax: +1-585-2731042
Received: May 29, 2015
Peer-review started: May 31, 2015
First decision: August 4, 2015
Revised: October 20, 2015
Accepted: November 23, 2015
Article in press: November 25, 2015
Published online: February 10, 2016
Processing time: 246 Days and 13.6 Hours


Platinum (Pt)-based antitumor agents are effective in the treatment of many solid malignancies. However, their efficacy is limited by toxicity and drug resistance. Reduced intracellular Pt accumulation has been consistently shown to correlate with resistance in tumors. Proteins involved in copper homeostasis have been identified as Pt transporters. In particular, copper transporter receptor 1 (CTR1), the major copper influx transporter, has been shown to play a significant role in Pt resistance. Clinical studies demonstrated that expression of CTR1 correlated with intratumoral Pt concentration and outcomes following Pt-based therapy. Other CTRs such as CTR2, ATP7A and ATP7B, may also play a role in Pt resistance. Recent clinical studies attempting to modulate CTR1 to overcome Pt resistance may provide novel strategies. This review discusses the role of CTR1 as a potential predictive biomarker of Pt sensitivity and a therapeutic target for overcoming Pt resistance.

Key Words: Resistance, Cisplatin, Copper transporter receptor 1, Copper transporter, Copper transporter receptor 2, ATP7A, ATP7B

Core tip: Platinum (Pt)-based chemotherapy is the backbone of treatment for various solid malignancies in both curative and palliative settings. However, the efficacy of Pt is limited by toxicity and inevitable resistance. Hence, it is important to understand the mechanisms of Pt resistance to not only identify treatment non-responders, but more importantly to help develop strategies to overcome resistance and improve efficacy. We herein discuss our current understanding of the mechanisms of Pt resistance, with a particular emphasis on the role of copper transporter receptor 1 in Pt resistance.

Role of platinum chemotherapeutics in cancer

Cisplatin, also called the “penicillin of cancer”, has remained the mainstay of treatment for a variety of solid tumors over the last four decades and is an essential component of both curative-intent and palliative chemotherapy regimens[1,2]. First described in 1845 as Peyrone’s salt and subsequently noted to inhibit binary fission in Escherichia coli bacteria, cisplatin is platinum (Pt)-based alkylating agent that binds to DNA and causes intra/inter strand crosslinking which interferes with cell division and causes apoptosis. Carboplatin and oxaliplatin are newer members of the Pt family of compounds with similar mechanisms of action as cisplatin but with different toxicity profiles.

Pt agents have a number of toxicities that limit their clinical use. The most common adverse effects from cisplatin include nephrotoxicity, ototoxicity, neurotoxicity and myelosuppression. Cisplatin is also highly emetogenic. Carboplatin is less emetogenic and has a lower risk of nephrotoxicity and ototoxicity; however, it is more myelosuppressive than other Pt compounds. Oxaliplatin which is significantly neurotoxic has the lowest risk of nephrotoxicity and ototoxicity amongst Pt compounds.

Despite the same class, each Pt drug has a unique role in the management of individual cancers, and in most circumstances these agents are not interchangeable. Cisplatin is the most active Pt agent against testicular, lung, ovarian and bladder cancers, and is the only Pt drug recommended in curative-intent treatment for these malignancies. In contrast, carboplatin may be substituted for cisplatin in the palliative setting for advanced solid tumors where cisplatin may not be tolerated due to adverse effects. In general, oxaliplatin is the Pt of choice for colon cancer.

Pt resistance is an inevitable occurrence with rare exception. Aside from germ cell tumors, metastatic solid tumors are generally thought to be incurable with cytotoxic chemotherapy due to the development of resistance and subsequent disease progression. While advances in molecular biology and genomic (personalized) medicine have driven an exponential increase in therapeutic options and improved outcome in various malignancies, Pt-based chemotherapy remains the backbone of treatment for a variety of solid tumors. Therefore, it is crucial to understand mechanisms of Pt resistance in order to develop strategies to overcome this nearly universal phenomenon.

Mechanisms of Pt resistance

The clinical utility of Pt agents is limited by both intrinsic and acquired resistance. For example, cisplatin-based treatment is associated with up to 80% response rates in patients with limited stage small cell lung cancer; however, the median overall survival is less than a year due to lack of durable response[3]. Understanding the mechanisms of Pt resistance may improve clinical outcomes. Pt resistance is complex and is regulated by a cascade of events that interfere with any of the multiple steps involved in its cytotoxic actions, from initial drug entry into the cell to the final stages of apoptosis. While not fully understood, identified mechanisms of resistance include: Increased glutathione and metallothionein, which inactivates the reactive forms of Pt[4-6], activation of nucleotide excision repair pathway and other pathways associated with DNA repair[7,8], and dysregulation of the tumor suppressor p53 gene that is required for apoptosis[9-12]. Dysregulation of the Ras and MAPK pathway[13,14] and the heat-shock proteins[15] have also been implicated in Pt resistance.

Despite the multifactorial nature of Pt resistance, reduced intracellular drug accumulation is one of the most consistently identified features of cisplatin-resistant cell lines[4,16]. Reduced influx or increased efflux of the drug is associated with decreased intracellular accumulation. Pt drug influx has been attributed to both non-saturable as well as energy-dependent active transport processes[17,18]. Currently identified Pt influx transporters include copper transporter receptor 1 (CTR1) and organic cation transporters belonging to the soluble carrier (SLC) SLC22A2 family. On the contrary increased levels of the multidrug resistance associated transporter protein MRP2 (cMOAT), adenosine triphosphate (ATP) binding cassette (ABC) multidrug transporters, CTR2 and copper-transporting P-type adenosine triphosphates (ATPase’s) have been observed to confer resistance[19,20]. In this review we will focus on the importance of intratumoral Pt levels in promoting chemosensitivity and the role of CTRs, specifically CTR1, in contributing to Pt resistance.


It has been hypothesized that reduced intracellular Pt concentration may confer resistance to Pt-based chemotherapy. Both in vitro and in vivo studies provide data to support this hypothesis.

In vitro studies

Lanzi et al[21], demonstrated that a reduction of drug accumulation in cisplatin-resistant (A431/Pt) human cervix squamous cell carcinoma compared to Pt-sensitive squamous cancer cells directly correlated with the extent of cisplatin-induced DNA damage. Mann et al[22], noted that, in human ovarian cancer cell lines, decreased Pt drug accumulation is associated with resistance. Several other investigators observed similar positive correlations between accumulation of Pt and cytotoxicity in cancer cell lines derived from ovarian, leukemia and lung cancer tissues[23-26]. All these studies support drug accumulation as a contributing factor to Pt resistance. However, cell line studies represent only a single phenotype and do not take into account complex tumor- host interaction that may allow for other mechanisms of chemoresistance.

In vivo studies

It has been demonstrated that the elimination of Pt compounds is triphasic in nature, with a terminal plasma half-life of 5.4 d for cisplatin. In contrast, Pt has a long half-life in human tissue that is yet to be quantified[27]. Pt and DNA adducts were detectable in autopsy tumor samples from patients who had received Pt up to 15 mo ante mortem[28,29]. In a prospective study of two groups of advanced non-small cell lung cancer (NSCLC) patients receiving cisplatin at two different doses, plasma Pt concentration correlated with the dose of cisplatin administered, however tissue Pt concentration did not. In this study there was a weak correlation between simultaneous plasma and tumor tissue concentration[30]. In 44 patients with NSCLC who had received neoadjuvant Pt-based therapy and subsequently underwent surgical resection, tissue Pt concentrations in resected tumor specimens significantly correlated with percent reduction in tumor (P < 0.001). The same correlations were seen irrespective of the Pt drug utilized, number of cycles and histologic subtype. Patients with higher intratumoral Pt concentrations also had longer time to recurrence (P = 0.034), progression-free survival (P = 0.018), and overall survival (P = 0.005). This was the first clinical study to establish a relationship between tissue Pt concentration and tumor response, and supports Pt accumulation as an important mechanism of resistance even in the clinical setting[31]. In another study of 19 patients with muscle invasive bladder cancer who had received Pt-based neoadjuvant therapy, total Pt concentration in normal adjacent bladder tissue significantly differed by tumor pathologic response (P = 0.011). Specimens with pathologic complete responses had the highest Pt concentrations compared to those with a down-staging to non-muscle invasive disease (P = 0.0095) or no response/progression (P = 0.0196)[32]. These findings suggest that intratumoral Pt accumulation may be an important determinant of Pt sensitivity and tumor responses across tumor types.


Pt chemotherapeutics cross the cell membranes by passive diffusion and transporters. Various ion pumps and transporters have been implicated in the transport of Pt agents, some of which are well-characterized[33]. More recently, transporters involved in copper homeostasis have been identified as important in Pt influx and efflux. Copper is an essential micronutrient and a cofactor for many enzymes. However, its intracellular form is highly toxic, and hence, a complex network of proteins have evolved to chaperone copper to the copper-dependent proteins. Chaperone proteins include CTR1, CTR2, antioxidant protein (ATOX 1), ATP7A and ATP7B. All of the above discussed transporters possess a metal binding sequence that binds both copper and Pt[34].

CTR1 is the most extensively studied Pt influx transporter and will be described in detail in the next section. CTR2, another copper uptake protein, has a substantial structural homology to CTR1but functions as a Pt efflux transporter. Higher CTR2 levels correlated with Pt resistance in ovarian cancer cell lines[35]. It was also noted that in a human 2008 epithelial cancer cell model, higher expression of CTR2 was noted to be associated with increased intracellular copper and Pt resistance[36]. Further studies are needed to better understand the role of CTR2 in cisplatin resistance in human cancers.

ATP7A and ATP7B are two copper transporting P-type ATPase that also maintain copper homeostasis and have been implicated in Pt efflux[37,38]. ATP7A is thought to regulate Pt accumulation, primarily by sequestering Pt intracellularly, whereas ATP7B located in the Trans Golgi network mediates Pt drug efflux via a process that involves its transport into vesicles involved in the secretory pathway[39]. In human epidermoid carcinoma KB-3-1 cell(a derivative of HELA–cervical cancer line), transfection with ATP7B conferred cisplatin resistance[40]. Similarly in prostate cell lines, overexpression of ATP7B correlated with Pt resistance[40]. The observation that human tumor cells transfected with ATP7B acquire resistance to cisplatin lends credence to the hypothesis that drug efflux plays a role in resistance[41]. Several cell line studies, including one of fibroblasts derived from a patient with Menkes disease, which is characterized by copper deficiency, confirmed the role of efflux proteins in enhancing Pt resistance[42,43]. ATP7B silencing resulted in enhanced cisplatin sensitivity and increased DNA adducts formation in cisplatin-resistant cells; however this was not observed with ATP7A silencing[44]. In both NSCLC xenografts exposed to cisplatin and colorectal cancer patients treated with oxaliplatin, increased levels of ATP7B were associated with Pt resistance[45,46]. In the only study to simultaneously assess influx and efflux transporters, expression of CRT1, ATP7A and ATP7B were measured in three pairs of parent cell lines and cisplatin-resistant cell lines derived from various types of invasive oral squamous cell carcinoma. ATP7B expression correlated with the acquisition of cisplatin resistance more closely than either CTR1 or ATPP7A[39].

Structure and localization

CTR1 is a 190 amino acid (aa) protein with three transmembrane domains, a approximately 67 aa extracellular N-terminal (ecto) domain, and a approximately 15 aa C-terminal cytosolic tail[47,48]. Crystallographic analysis of human CTR1 noted that the permeation conduit formed by the association of three CTR1 molecules involves a series of rings of methionines capable of chelating copper in a trimeric configuration[48,49]. Two rings each containing three methionines are stacked on top of each other in the narrowest part of the pore, and a ring of three cysteines is located at the bottom of the pore. The aperture has a truncated cone shape measuring approximately equal 8 Å at the external entrance and approximately equal 22 Å at the intracellular end[50]. The expression of CTR1 is ubiquitous and localizes to the plasma membrane in some cell lines and perinuclear vesicles in others[51].

Role in copper transport

CTR1 is the primary influx transporter of copper in human cells. Transport of copper by CTR1 is energy-independent[52] and results in conformational changes in CTR1[53]. Knockout of both CTR1 alleles results in an embryonic lethal phenotype thought to be secondary to deficiency of copper[54]. Organ-specific knockout of CTR1 in the intestine and liver confirms the role of CTR1 as an important copper transporter[55,56]. The exact mechanism of copper transport across CTR1 is not yet completely understood and further studies are warranted.


Despite the “narrowest opening” of trimetric CTR1 being smaller than the molecular size of cisplatin, studies suggest that prior to entering a cell, cisplatin is activated by interacting with the extracellular methionine clusters of CTR1, which results in the formation of an intermediate that is smaller than the radius of the narrowest opening CTR1[57,58].

In vitro studies

Ishida et al[59], described CTR1 as a significant uptake transporter of cisplatin. They used a mutagenized wild type yeast cell library to select for mutants that grew in the presence of toxic doses of cisplatin. Cells with a CTR1 mutation that decreased CTR1 cell expression were noted to have profound Pt resistance compared to other mutants. In order to determine the mechanistic role of CTR1 in cisplatin resistance, cisplatin - DNA adducts were measured. They observed that decreased Pt uptake is responsible for lower Pt adduct levels and resistance. They also demonstrated that cisplatin, similar to copper, down-regulated CTR1 expression in yeast cell lines.

CTR1 knockout in intestinal epithelial mouse cell lines also led to a decrease in intracellular Pt levels and resistance[60]. Similarly, overexpression of CTR1 was associated with cisplatin sensitivity in ovarian and colorectal cancer cell lines[61,62]. In cisplatin-resistant small cell lung cancer cells, sensitivity was restored when CTR1 was introduced into these cells[63]. Ivy et al[64] also noted that higher intracellular Pt correlated with higher CTR1 levels in human embryonic kidney cells and mouse embryonic fibroblasts. However contrary to other studies, the investigators noted that in ovarian tumor cells uptake of Pt was linear and non-saturable, suggesting that there could be other mechanisms besides CTR1 involved in Pt transport, including proteins involved in copper homeostasis[64].

In vivo studies

In rat dorsal root ganglion, CTR1 expression by immunohistochemistry (IHC) and RT-PCR correlated with Pt uptake and treatment-induced cell body atrophy[65]. Similarly, in a murine model utilizing mouse embryo fibroblasts, CTR1 knockout completely eliminated responsiveness of cells to Pt agents[66]. In a mouse model of human cervical cancer (HPV16/E ), the levels of cisplatin-induced DNA adducts correlated with CTR1 mRNA in most organs tested, including skin, lung, liver, pancreas, and uterus[67].


To date, several human studies have investigated the role of CTR1 in Pt sensitivity. In 15 patients with stage III/IV serous epithelial ovarian tumors who underwent optimal cytoreductive surgery (residual masses 1 cm or less) and subsequent Pt-based therapy, tumor CTR1 mRNA correlated with Pt sensitivity. Patients with no evidence of disease progression within 6 mo had higher CTR1 mRNA levels than in patients with refractory or resistant disease. Using clinical and array based expression data from the cancer genome atlas; the same investigators were able to independently validate the correlation of CTR1 m RNA levels with clinical outcomes in patients with advanced ovarian tumors who also underwent Pt-based therapy[67]. Higher CTR1 expression by IHC in patients with stage III endometrial cancer who had received carboplatin also correlated with longer disease free and overall survival (P = 0.009)[68].

In a study of 30 patients with NSCLC who had received neoadjuvant Pt-based chemotherapy, patients with undetectable CTR1 expression in their tumors had reduced intratumoral Pt concentrations and tumor response[69]. In another study of 54 patients with stage III non-small lung cancer who received Pt-based combination chemotherapy, higher CTR1 expression correlated with longer progression free survival and overall survival (P = 0.01 and 0.047, respectively)[70]. More recently, we demonstrated that tumor CTR1 expression in cystectomy specimens of patients with muscle invasive bladder cancer correlated significantly with pathologic downstaging after Pt- based neoadjuvant chemotherapy[71].


CTR1 expression has been shown to be regulated at both transcriptional and post-translational levels by various factors including transcription factor specificity protein 1 (Sp1) as well as copper and other heavy metals such as Cd, Zn and Ag[72,73]. Sp1 is a zinc finger transcription factor that binds to GC-rich motifs in promoters and is involved in many cellular processes including cell differentiation, cell growth, apoptosis, immune responses and response to DNA damage. Song et al[74] demonstrated that three binding sites in the CTR1 promoter of Sp1 are involved in the basal and copper concentration-dependent regulation of CTR1 expression. The zinc-finger domain of Sp1 serves as a sensor of copper that regulates CTR1 expression in response to fluctuations in copper concentration[74,75]. In addition, modulation of Sp1 levels also affected the expression of CTR1. Cisplatin competes with copper for CTR1-mediated transport and trigger the rapid degradation of CTR1. It has been postulated that this mechanism serves to limit the toxic accumulation of the metal that it transports[76,77]. The down-regulation of CTR1 expression after Pt exposure has been confirmed in various cell lines and is considered functionally significant as subsequent copper uptake, despite Pt absence, is noted to be decreased[49,77].

In a study of 282 Chinese patients with NSCLC who received Pt-based therapy, genetic polymorphisms of CTR1 at reference single nucleotide polymorphism (rs) rs7851395 and rs12686377 were associated with Pt resistance and poor clinical outcomes. Patients with a GT haplotype had increased susceptibility to Pt resistance, whereas AG haplotype conferred longer overall survival[78]. In a second study of 204 Chinese patients, CTR1 polymorphism (rs10981694 A > C) correlated with Pt toxicity in patients with advanced stage NSCLC and could be potentially used for pretreatment evaluation of toxicity. However, the survival times of patients with different rs10981694 genetic polymorphisms were not significantly different[72]. Functional implications of these polymorphisms are not clear.


Cisplatin-induced degradation of CTR1 was noted to be reversible with the proteasome inhibitor bortezomib in both mouse fibroblast and human ovarian carcinoma cell lines. This in turn correlated with increased cellular uptake and the cytotoxicity of cisplatin in a synergistic manner[73]. Cells lacking CTR1 had no change in cisplatin uptake with bortezomib suggesting that bortezomib may act primarily through blocking CTR1 degradation. NCT01074411 is an ongoing phase 1 trial of intraperitoneal bortezomib and carboplatin that tests this hypothesis in patients with recurrent ovarian cancer.

Ag and zinc have been noted to induce CTR1 expression. In CTR1-transfected or nontransfected HEK293 cells Ag, Zn inhibited CTR1-mediated copper uptake[52]. Also in IGROV1 and SKOV-3 cells treated with different concentrations of Zn, and Ag, there was a concentration-dependent increase in expression of CTR1 and Sp1[79]. In a double-blind, placebo-controlled study of 34 patients with stage III/IV nasopharyngeal carcinoma receiving cisplatin-based chemotherapy, zinc supplement (75 mg/d) was associated with longer overall survival, local-free survival and disease-free survival compared with placebo (P = 0.044, P = 0.007, and P = 0.033, respectively)[77]. More recently in ovarian cancer cells and xenograft mice, (-)-epigallocatechin-3-gallate (EGCG), a major polyphenol from green tea was noted to increase CTR1 m RNA and protein expression. These findings translated into EGCG enhancing the sensitivity of ovarian cancer SKOV3 and OVCAR3 cells to Pt through increased Pt accumulation and DNA-Pt adducts[80]. Copper chelators are a class of compounds that preferentially bind either cuprous or cupric forms of copper and potentially modulate copper redox-activity without removing copper from the system. They are characterized as either membrane-permeable or - impermeable and serve as an organ-selective copper delivery or deprivation system to manipulate the biological function of copper. Tetrathiomolybdate (TTM), a specific and effective copper chelator was initially developed as a therapeutic agent to treat Wilson’s disease, which is characterized by excessive copper accumulation in liver and brain[81]. TTM demonstrates antiangiogenic, antifibrogenic, and anti-inflammatory actions in preclinical studies. While TTM has a good safety index, most of its toxicity in animals is due to copper deficiency that is easily reversible with acute copper supplementation[82]. Daily treatment with TTM has been shown to safely reduce bioavailable copper in 2-4 wk in humans and mice, likely through formation of a high-affinity tripartite complex with copper and proteins[83]. Liang et al[76] demonstrated that in cisplatin-resistant ovarian cancer cell lines derived from patients, resistance associated with reduced expression of the CTR1 could be overcome by copper-lowering agents (TTM, D-penicillamine and trientine) which enhanced CTR1 expression. In a murine model of human cervical cancer, combined therapy with TTM and cisplatin enhanced therapeutic efficacy by increasing tumor-specific uptake of Pt[67]. Similarly, in oxaliplatin-resistant cell lines derived from human cervical carcinoma, D-penicillamine in combination with cisplatin and oxaliplatin overcomes resistance through increased CTR1 expression by up regulation of Sp1[84]. These studies provided the mechanistic rationale for using copper chelation to overcome Pt resistance in cancer patients. Trientine was combined with carboplatin in ovarian cancer patients[85]. NCT01837329 is an ongoing phase 1 study combining TTM with Pt-doublet in advanced NSCLC patients. Further studies are needed to validate these findings in order to use the above agents as adjuncts to conventional Pt based therapy and improve outcomes.


Pt-based chemotherapy is the backbone of both curative and palliative treatment for numerous malignancies. Copper transporters, in particular CTR1, play a significant role in intracellular Pt accumulation and have the potential to be used as predictive biomarkers of Pt sensitivity. In addition, modulation of copper transporter expression may be a novel therapeutic strategy to enhance the efficacy of Pt chemotherapy by increasing intratumoral Pt concentration. Specifically, copper chelators and agents that prevent degradation of CTR1, such as bortezomib, are currently being studied in combination with Pt in a variety of solid tumors known to develop Pt resistance.


P- Reviewer: Ragazzi E, Wiemer EAC S- Editor: Ji FF L- Editor: A E- Editor: Jiao XK

1.  Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, deVere White RW, Sarosdy MF, Wood DP, Raghavan D. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003;349:859-866.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1879]  [Cited by in F6Publishing: 1905]  [Article Influence: 90.7]  [Reference Citation Analysis (0)]
2.  Feldman DR, Bosl GJ, Sheinfeld J, Motzer RJ. Medical treatment of advanced testicular cancer. JAMA. 2008;299:672-684.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 262]  [Cited by in F6Publishing: 272]  [Article Influence: 17.0]  [Reference Citation Analysis (0)]
3.  Fukuoka M, Furuse K, Saijo N, Nishiwaki Y, Ikegami H, Tamura T, Shimoyama M, Suemasu K. Randomized trial of cyclophosphamide, doxorubicin, and vincristine versus cisplatin and etoposide versus alternation of these regimens in small-cell lung cancer. J Natl Cancer Inst. 1991;83:855-861.  [PubMed]  [DOI]  [Cited in This Article: ]
4.  Kelland LR. New platinum antitumor complexes. Crit Rev Oncol Hematol. 1993;15:191-219.  [PubMed]  [DOI]  [Cited in This Article: ]
5.  Wolf CR, Hayward IP, Lawrie SS, Buckton K, McIntyre MA, Adams DJ, Lewis AD, Scott AR, Smyth JF. Cellular heterogeneity and drug resistance in two ovarian adenocarcinoma cell lines derived from a single patient. Int J Cancer. 1987;39:695-702.  [PubMed]  [DOI]  [Cited in This Article: ]
6.  Kasahara K, Fujiwara Y, Nishio K, Ohmori T, Sugimoto Y, Komiya K, Matsuda T, Saijo N. Metallothionein content correlates with the sensitivity of human small cell lung cancer cell lines to cisplatin. Cancer Res. 1991;51:3237-3242.  [PubMed]  [DOI]  [Cited in This Article: ]
7.  Chaney SG, Sancar A. DNA repair: enzymatic mechanisms and relevance to drug response. J Natl Cancer Inst. 1996;88:1346-1360.  [PubMed]  [DOI]  [Cited in This Article: ]
8.  Furuta T, Ueda T, Aune G, Sarasin A, Kraemer KH, Pommier Y. Transcription-coupled nucleotide excision repair as a determinant of cisplatin sensitivity of human cells. Cancer Res. 2002;62:4899-4902.  [PubMed]  [DOI]  [Cited in This Article: ]
9.  Siddik ZH, Hagopian GS, Thai G, Tomisaki S, Toyomasu T, Khokhar AR. Role of p53 in the ability of 1,2-diaminocyclohexane-diacetato-dichloro-Pt(IV) to circumvent cisplatin resistance. J Inorg Biochem. 1999;77:65-70.  [PubMed]  [DOI]  [Cited in This Article: ]
10.  Righetti SC, Perego P, Corna E, Pierotti MA, Zunino F. Emergence of p53 mutant cisplatin-resistant ovarian carcinoma cells following drug exposure: spontaneously mutant selection. Cell Growth Differ. 1999;10:473-478.  [PubMed]  [DOI]  [Cited in This Article: ]
11.  Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science. 1991;253:49-53.  [PubMed]  [DOI]  [Cited in This Article: ]
12.  Houldsworth J, Xiao H, Murty VV, Chen W, Ray B, Reuter VE, Bosl GJ, Chaganti RS. Human male germ cell tumor resistance to cisplatin is linked to TP53 gene mutation. Oncogene. 1998;16:2345-2349.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 124]  [Cited by in F6Publishing: 128]  [Article Influence: 4.9]  [Reference Citation Analysis (0)]
13.  Mandic A, Viktorsson K, Heiden T, Hansson J, Shoshan MC. The MEK1 inhibitor PD98059 sensitizes C8161 melanoma cells to cisplatin-induced apoptosis. Melanoma Res. 2001;11:11-19.  [PubMed]  [DOI]  [Cited in This Article: ]
14.  Holford J, Rogers P, Kelland LR. ras mutation and platinum resistance in human ovarian carcinomas in vitro. Int J Cancer. 1998;77:94-100.  [PubMed]  [DOI]  [Cited in This Article: ]
15.  Yamamoto K, Okamoto A, Isonishi S, Ochiai K, Ohtake Y. Heat shock protein 27 was up-regulated in cisplatin resistant human ovarian tumor cell line and associated with the cisplatin resistance. Cancer Lett. 2001;168:173-181.  [PubMed]  [DOI]  [Cited in This Article: ]
16.  Andrews PA, Howell SB. Cellular pharmacology of cisplatin: perspectives on mechanisms of acquired resistance. Cancer Cells. 1990;2:35-43.  [PubMed]  [DOI]  [Cited in This Article: ]
17.  Yoshida M, Khokhar AR, Siddik ZH. Biochemical pharmacology of homologous alicyclic mixed amine platinum(II) complexes in sensitive and resistant tumor cell lines. Cancer Res. 1994;54:3468-3473.  [PubMed]  [DOI]  [Cited in This Article: ]
18.  Gately DP, Howell SB. Cellular accumulation of the anticancer agent cisplatin: a review. Br J Cancer. 1993;67:1171-1176.  [PubMed]  [DOI]  [Cited in This Article: ]
19.  Kool M, de Haas M, Scheffer GL, Scheper RJ, van Eijk MJ, Juijn JA, Baas F, Borst P. Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines. Cancer Res. 1997;57:3537-3547.  [PubMed]  [DOI]  [Cited in This Article: ]
20.  Burger H, Loos WJ, Eechoute K, Verweij J, Mathijssen RH, Wiemer EA. Drug transporters of platinum-based anticancer agents and their clinical significance. Drug Resist Updat. 2011;14:22-34.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 161]  [Cited by in F6Publishing: 164]  [Article Influence: 12.6]  [Reference Citation Analysis (0)]
21.  Lanzi C, Perego P, Supino R, Romanelli S, Pensa T, Carenini N, Viano I, Colangelo D, Leone R, Apostoli P. Decreased drug accumulation and increased tolerance to DNA damage in tumor cells with a low level of cisplatin resistance. Biochem Pharmacol. 1998;55:1247-1254.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 44]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
22.  Mann SC, Andrews PA, Howell SB. Short-term cis-diamminedichloroplatinum(II) accumulation in sensitive and resistant human ovarian carcinoma cells. Cancer Chemother Pharmacol. 1990;25:236-240.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 68]  [Cited by in F6Publishing: 75]  [Article Influence: 2.2]  [Reference Citation Analysis (0)]
23.  Andrews PA, Velury S, Mann SC, Howell SB. cis-Diamminedichloroplatinum(II) accumulation in sensitive and resistant human ovarian carcinoma cells. Cancer Res. 1988;48:68-73.  [PubMed]  [DOI]  [Cited in This Article: ]
24.  Eichholtz-Wirth H, Hietel B. The relationship between cisplatin sensitivity and drug uptake into mammalian cells in vitro. Br J Cancer. 1986;54:239-243.  [PubMed]  [DOI]  [Cited in This Article: ]
25.  Hromas RA, North JA, Burns CP. Decreased cisplatin uptake by resistant L1210 leukemia cells. Cancer Lett. 1987;36:197-201.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 34]  [Cited by in F6Publishing: 40]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
26.  Shellard SA, Fichtinger-Schepman AM, Lazo JS, Hill BT. Evidence of differential cisplatin-DNA adduct formation, removal and tolerance of DNA damage in three human lung carcinoma cell lines. Anticancer Drugs. 1993;4:491-500.  [PubMed]  [DOI]  [Cited in This Article: ]
27.  Vermorken JB, van der Vijgh WJ, Klein I, Hart AA, Gall HE, Pinedo HM. Pharmacokinetics of free and total platinum species after short-term infusion of cisplatin. Cancer Treat Rep. 1984;68:505-513.  [PubMed]  [DOI]  [Cited in This Article: ]
28.  Poirier MC, Reed E, Litterst CL, Katz D, Gupta-Burt S. Persistence of platinum-ammine-DNA adducts in gonads and kidneys of rats and multiple tissues from cancer patients. Cancer Res. 1992;52:149-153.  [PubMed]  [DOI]  [Cited in This Article: ]
29.  Stewart DJ, Benjamin RS, Luna M, Feun L, Caprioli R, Seifert W, Loo TL. Human tissue distribution of platinum after cis-diamminedichloroplatinum. Cancer Chemother Pharmacol. 1982;10:51-54.  [PubMed]  [DOI]  [Cited in This Article: ]
30.  Pujol JL, Cupissol D, Gestin-Boyer C, Bres J, Serrou B, Michel FB. Tumor-tissue and plasma concentrations of platinum during chemotherapy of non-small-cell lung cancer patients. Cancer Chemother Pharmacol. 1990;27:72-75.  [PubMed]  [DOI]  [Cited in This Article: ]
31.  Kim ES, Lee JJ, He G, Chow CW, Fujimoto J, Kalhor N, Swisher SG, Wistuba II, Stewart DJ, Siddik ZH. Tissue platinum concentration and tumor response in non-small-cell lung cancer. J Clin Oncol. 2012;30:3345-3352.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 66]  [Cited by in F6Publishing: 77]  [Article Influence: 6.4]  [Reference Citation Analysis (1)]
32.  Guancial EA, Kilari D, Messing EM, Kim ES. Platinum concentration in bladder tissue treated with neoadjuvant chemotherapy and pathologic responsee. ASCO Meeting Abstracts, 2015; 33: 341.  Available from:  [PubMed]  [DOI]  [Cited in This Article: ]
33.  Hall MD, Okabe M, Shen DW, Liang XJ, Gottesman MM. The role of cellular accumulation in determining sensitivity to platinum-based chemotherapy. Annu Rev Pharmacol Toxicol. 2008;48:495-535.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 351]  [Cited by in F6Publishing: 350]  [Article Influence: 21.9]  [Reference Citation Analysis (0)]
34.  Rae TD, Schmidt PJ, Pufahl RA, Culotta VC, O’Halloran TV. Undetectable intracellular free copper: the requirement of a copper chaperone for superoxide dismutase. Science. 1999;284:805-808.  [PubMed]  [DOI]  [Cited in This Article: ]
35.  Blair BG, Larson CA, Adams PL, Abada PB, Safaei R, Howell SB. Regulation of copper transporter 2 expression by copper and cisplatin in human ovarian carcinoma cells. Mol Pharmacol. 2010;77:912-921.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 35]  [Cited by in F6Publishing: 37]  [Article Influence: 2.6]  [Reference Citation Analysis (0)]
36.  Huang CP, Fofana M, Chan J, Chang CJ, Howell SB. Copper transporter 2 regulates intracellular copper and sensitivity to cisplatin. Metallomics. 2014;6:654-661.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 37]  [Article Influence: 3.7]  [Reference Citation Analysis (0)]
37.  Safaei R, Otani S, Larson BJ, Rasmussen ML, Howell SB. Transport of cisplatin by the copper efflux transporter ATP7B. Mol Pharmacol. 2008;73:461-468.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 82]  [Cited by in F6Publishing: 84]  [Article Influence: 4.9]  [Reference Citation Analysis (0)]
38.  Samimi G, Safaei R, Katano K, Holzer AK, Rochdi M, Tomioka M, Goodman M, Howell SB. Increased expression of the copper efflux transporter ATP7A mediates resistance to cisplatin, carboplatin, and oxaliplatin in ovarian cancer cells. Clin Cancer Res. 2004;10:4661-4669.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 221]  [Cited by in F6Publishing: 235]  [Article Influence: 12.4]  [Reference Citation Analysis (0)]
39.  Yoshizawa K, Nozaki S, Kitahara H, Ohara T, Kato K, Kawashiri S, Yamamoto E. Copper efflux transporter (ATP7B) contributes to the acquisition of cisplatin-resistance in human oral squamous cell lines. Oncol Rep. 2007;18:987-991.  [PubMed]  [DOI]  [Cited in This Article: ]
40.  Komatsu M, Sumizawa T, Mutoh M, Chen ZS, Terada K, Furukawa T, Yang XL, Gao H, Miura N, Sugiyama T. Copper-transporting P-type adenosine triphosphatase (ATP7B) is associated with cisplatin resistance. Cancer Res. 2000;60:1312-1316.  [PubMed]  [DOI]  [Cited in This Article: ]
41.  Nakayama K, Kanzaki A, Ogawa K, Miyazaki K, Neamati N, Takebayashi Y. Copper-transporting P-type adenosine triphosphatase (ATP7B) as a cisplatin based chemoresistance marker in ovarian carcinoma: comparative analysis with expression of MDR1, MRP1, MRP2, LRP and BCRP. Int J Cancer. 2002;101:488-495.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 106]  [Cited by in F6Publishing: 112]  [Article Influence: 5.1]  [Reference Citation Analysis (0)]
42.  Samimi G, Katano K, Holzer AK, Safaei R, Howell SB. Modulation of the cellular pharmacology of cisplatin and its analogs by the copper exporters ATP7A and ATP7B. Mol Pharmacol. 2004;66:25-32.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 118]  [Cited by in F6Publishing: 117]  [Article Influence: 5.9]  [Reference Citation Analysis (0)]
43.  Katano K, Kondo A, Safaei R, Holzer A, Samimi G, Mishima M, Kuo YM, Rochdi M, Howell SB. Acquisition of resistance to cisplatin is accompanied by changes in the cellular pharmacology of copper. Cancer Res. 2002;62:6559-6565.  [PubMed]  [DOI]  [Cited in This Article: ]
44.  Mangala LS, Zuzel V, Schmandt R, Leshane ES, Halder JB, Armaiz-Pena GN, Spannuth WA, Tanaka T, Shahzad MM, Lin YG. Therapeutic Targeting of ATP7B in Ovarian Carcinoma. Clin Cancer Res. 2009;15:3770-3780.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 96]  [Cited by in F6Publishing: 109]  [Article Influence: 7.3]  [Reference Citation Analysis (0)]
45.  Nakagawa T, Inoue Y, Kodama H, Yamazaki H, Kawai K, Suemizu H, Masuda R, Iwazaki M, Yamada S, Ueyama Y. Expression of copper-transporting P-type adenosine triphosphatase (ATP7B) correlates with cisplatin resistance in human non-small cell lung cancer xenografts. Oncol Rep. 2008;20:265-270.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3]  [Cited by in F6Publishing: 3]  [Article Influence: 0.2]  [Reference Citation Analysis (0)]
46.  Martinez-Balibrea E, Martínez-Cardús A, Musulén E, Ginés A, Manzano JL, Aranda E, Plasencia C, Neamati N, Abad A. Increased levels of copper efflux transporter ATP7B are associated with poor outcome in colorectal cancer patients receiving oxaliplatin-based chemotherapy. Int J Cancer. 2009;124:2905-2910.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 41]  [Cited by in F6Publishing: 50]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
47.  Aller SG, Eng ET, De Feo CJ, Unger VM. Eukaryotic CTR copper uptake transporters require two faces of the third transmembrane domain for helix packing, oligomerization, and function. J Biol Chem. 2004;279:53435-53441.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 86]  [Cited by in F6Publishing: 86]  [Article Influence: 4.3]  [Reference Citation Analysis (0)]
48.  De Feo CJ, Aller SG, Siluvai GS, Blackburn NJ, Unger VM. Three-dimensional structure of the human copper transporter hCTR1. Proc Natl Acad Sci USA. 2009;106:4237-4242.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 207]  [Cited by in F6Publishing: 210]  [Article Influence: 14.0]  [Reference Citation Analysis (0)]
49.  De Feo CJ, Aller SG, Unger VM. A structural perspective on copper uptake in eukaryotes. Biometals. 2007;20:705-716.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 60]  [Cited by in F6Publishing: 60]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
50.  Klomp AE, Tops BB, Van Denberg IE, Berger R, Klomp LW. Biochemical characterization and subcellular localization of human copper transporter 1 (hCTR1). Biochem J. 2002;364:497-505.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 149]  [Cited by in F6Publishing: 153]  [Article Influence: 7.0]  [Reference Citation Analysis (0)]
51.  Zhou B, Gitschier J. hCTR1: a human gene for copper uptake identified by complementation in yeast. Proc Natl Acad Sci USA. 1997;94:7481-7486.  [PubMed]  [DOI]  [Cited in This Article: ]
52.  Lee J, Peña MM, Nose Y, Thiele DJ. Biochemical characterization of the human copper transporter Ctr1. J Biol Chem. 2002;277:4380-4387.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 447]  [Cited by in F6Publishing: 435]  [Article Influence: 19.8]  [Reference Citation Analysis (0)]
53.  Sinani D, Adle DJ, Kim H, Lee J. Distinct mechanisms for Ctr1-mediated copper and cisplatin transport. J Biol Chem. 2007;282:26775-26785.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 77]  [Cited by in F6Publishing: 80]  [Article Influence: 4.7]  [Reference Citation Analysis (0)]
54.  Kuo YM, Zhou B, Cosco D, Gitschier J. The copper transporter CTR1 provides an essential function in mammalian embryonic development. Proc Natl Acad Sci USA. 2001;98:6836-6841.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 279]  [Cited by in F6Publishing: 270]  [Article Influence: 11.7]  [Reference Citation Analysis (0)]
55.  Nose Y, Kim BE, Thiele DJ. Ctr1 drives intestinal copper absorption and is essential for growth, iron metabolism, and neonatal cardiac function. Cell Metab. 2006;4:235-244.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 211]  [Cited by in F6Publishing: 207]  [Article Influence: 11.5]  [Reference Citation Analysis (0)]
56.  Kim H, Son HY, Bailey SM, Lee J. Deletion of hepatic Ctr1 reveals its function in copper acquisition and compensatory mechanisms for copper homeostasis. Am J Physiol Gastrointest Liver Physiol. 2009;296:G356-G364.  [PubMed]  [DOI]  [Cited in This Article: ]
57.  Sze CM, Khairallah GN, Xiao Z, Donnelly PS, O’Hair RA, Wedd AG. Interaction of cisplatin and analogues with a Met-rich protein site. J Biol Inorg Chem. 2009;14:163-165.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 29]  [Cited by in F6Publishing: 30]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
58.  Wu Z, Liu Q, Liang X, Yang X, Wang N, Wang X, Sun H, Lu Y, Guo Z. Reactivity of platinum-based antitumor drugs towards a Met- and His-rich 20mer peptide corresponding to the N-terminal domain of human copper transporter 1. J Biol Inorg Chem. 2009;14:1313-1323.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 69]  [Cited by in F6Publishing: 69]  [Article Influence: 4.6]  [Reference Citation Analysis (0)]
59.  Ishida S, Lee J, Thiele DJ, Herskowitz I. Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals. Proc Natl Acad Sci USA. 2002;99:14298-14302.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 647]  [Cited by in F6Publishing: 642]  [Article Influence: 29.2]  [Reference Citation Analysis (0)]
60.  Lee J, Petris MJ, Thiele DJ. Characterization of mouse embryonic cells deficient in the ctr1 high affinity copper transporter. Identification of a Ctr1-independent copper transport system. J Biol Chem. 2002;277:40253-40259.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 183]  [Cited by in F6Publishing: 180]  [Article Influence: 8.2]  [Reference Citation Analysis (0)]
61.  Holzer AK, Samimi G, Katano K, Naerdemann W, Lin X, Safaei R, Howell SB. The copper influx transporter human copper transport protein 1 regulates the uptake of cisplatin in human ovarian carcinoma cells. Mol Pharmacol. 2004;66:817-823.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 160]  [Cited by in F6Publishing: 167]  [Article Influence: 8.4]  [Reference Citation Analysis (0)]
62.  Noordhuis P, Laan AC, van de Born K, Losekoot N, Kathmann I, Peters GJ. Oxaliplatin activity in selected and unselected human ovarian and colorectal cancer cell lines. Biochem Pharmacol. 2008;76:53-61.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 31]  [Cited by in F6Publishing: 31]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
63.  Song IS, Savaraj N, Siddik ZH, Liu P, Wei Y, Wu CJ, Kuo MT. Role of human copper transporter Ctr1 in the transport of platinum-based antitumor agents in cisplatin-sensitive and cisplatin-resistant cells. Mol Cancer Ther. 2004;3:1543-1549.  [PubMed]  [DOI]  [Cited in This Article: ]
64.  Ivy KD, Kaplan JH. A re-evaluation of the role of hCTR1, the human high-affinity copper transporter, in platinum-drug entry into human cells. Mol Pharmacol. 2013;83:1237-1246.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 59]  [Cited by in F6Publishing: 60]  [Article Influence: 5.5]  [Reference Citation Analysis (0)]
65.  Liu JJ, Jamieson SM, Subramaniam J, Ip V, Jong NN, Mercer JF, McKeage MJ. Neuronal expression of copper transporter 1 in rat dorsal root ganglia: association with platinum neurotoxicity. Cancer Chemother Pharmacol. 2009;64:847-856.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 44]  [Article Influence: 2.9]  [Reference Citation Analysis (0)]
66.  Larson CA, Blair BG, Safaei R, Howell SB. The role of the mammalian copper transporter 1 in the cellular accumulation of platinum-based drugs. Mol Pharmacol. 2009;75:324-330.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 123]  [Cited by in F6Publishing: 127]  [Article Influence: 7.9]  [Reference Citation Analysis (0)]
67.  Ishida S, McCormick F, Smith-McCune K, Hanahan D. Enhancing tumor-specific uptake of the anticancer drug cisplatin with a copper chelator. Cancer Cell. 2010;17:574-583.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 215]  [Cited by in F6Publishing: 214]  [Article Influence: 15.3]  [Reference Citation Analysis (0)]
68.  Ogane N, Yasuda M, Kameda Y, Yokose T, Kato H, Itoh A, Nishino S, Hashimoto Y, Kamoshida S. Prognostic value of organic anion transporting polypeptide 1B3 and copper transporter 1 expression in endometrial cancer patients treated with paclitaxel and carboplatin. Biomed Res. 2013;34:143-151.  [PubMed]  [DOI]  [Cited in This Article: ]
69.  Kim ES, Tang X, Peterson DR, Kilari D, Chow CW, Fujimoto J, Kalhor N, Swisher SG, Stewart DJ, Wistuba II. Copper transporter CTR1 expression and tissue platinum concentration in non-small cell lung cancer. Lung Cancer. 2014;85:88-93.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 45]  [Cited by in F6Publishing: 56]  [Article Influence: 5.6]  [Reference Citation Analysis (0)]
70.  Chen HH, Yan JJ, Chen WC, Kuo MT, Lai YH, Lai WW, Liu HS, Su WC. Predictive and prognostic value of human copper transporter 1 (hCtr1) in patients with stage III non-small-cell lung cancer receiving first-line platinum-based doublet chemotherapy. Lung Cancer. 2012;75:228-234.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 56]  [Cited by in F6Publishing: 56]  [Article Influence: 4.3]  [Reference Citation Analysis (0)]
71.  Kilari D, Iczkowski K, Robin A, Pandya C, Bylow KA, Langenstroer P, Messing EM, Guancial EA, Kim ES. Association between copper transporter receptor 1(ctr1) expression and pathologic outcomes in cisplatin (pt)-treated bladder cancer (bc) patients. ASCO Meeting Abstracts 2014; 32: e15516.  Available from:  [PubMed]  [DOI]  [Cited in This Article: ]
72.  Xu X, Ren H, Zhou B, Zhao Y, Yuan R, Ma R, Zhou H, Liu Z. Prediction of copper transport protein 1 (CTR1) genotype on severe cisplatin induced toxicity in non-small cell lung cancer (NSCLC) patients. Lung Cancer. 2012;77:438-442.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 46]  [Cited by in F6Publishing: 48]  [Article Influence: 4.0]  [Reference Citation Analysis (0)]
73.  Jandial DD, Farshchi-Heydari S, Larson CA, Elliott GI, Wrasidlo WJ, Howell SB. Enhanced delivery of cisplatin to intraperitoneal ovarian carcinomas mediated by the effects of bortezomib on the human copper transporter 1. Clin Cancer Res. 2009;15:553-560.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 63]  [Cited by in F6Publishing: 66]  [Article Influence: 4.4]  [Reference Citation Analysis (0)]
74.  Song IS, Chen HH, Aiba I, Hossain A, Liang ZD, Klomp LW, Kuo MT. Transcription factor Sp1 plays an important role in the regulation of copper homeostasis in mammalian cells. Mol Pharmacol. 2008;74:705-713.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 65]  [Cited by in F6Publishing: 73]  [Article Influence: 4.6]  [Reference Citation Analysis (0)]
75.  Liang ZD, Tsai WB, Lee MY, Savaraj N, Kuo MT. Specificity protein 1 (sp1) oscillation is involved in copper homeostasis maintenance by regulating human high-affinity copper transporter 1 expression. Mol Pharmacol. 2012;81:455-464.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 45]  [Cited by in F6Publishing: 66]  [Article Influence: 5.1]  [Reference Citation Analysis (0)]
76.  Liang ZD, Long Y, Tsai WB, Fu S, Kurzrock R, Gagea-Iurascu M, Zhang F, Chen HH, Hennessy BT, Mills GB. Mechanistic basis for overcoming platinum resistance using copper chelating agents. Mol Cancer Ther. 2012;11:2483-2494.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 60]  [Cited by in F6Publishing: 58]  [Article Influence: 4.8]  [Reference Citation Analysis (0)]
77.  Lin YS, Lin LC, Lin SW. Effects of zinc supplementation on the survival of patients who received concomitant chemotherapy and radiotherapy for advanced nasopharyngeal carcinoma: follow-up of a double-blind randomized study with subgroup analysis. Laryngoscope. 2009;119:1348-1352.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 27]  [Cited by in F6Publishing: 29]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
78.  Xu X, Duan L, Zhou B, Ma R, Zhou H, Liu Z. Genetic polymorphism of copper transporter protein 1 is related to platinum resistance in Chinese non-small cell lung carcinoma patients. Clin Exp Pharmacol Physiol. 2012;39:786-792.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 41]  [Article Influence: 3.7]  [Reference Citation Analysis (0)]
79.  Liang ZD, Long Y, Chen HH, Savaraj N, Kuo MT. Regulation of the high-affinity copper transporter (hCtr1) expression by cisplatin and heavy metals. J Biol Inorg Chem. 2014;19:17-27.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 17]  [Cited by in F6Publishing: 17]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
80.  Wang X, Jiang P, Wang P, Yang CS, Wang X, Feng Q. EGCG Enhances Cisplatin Sensitivity by Regulating Expression of the Copper and Cisplatin Influx Transporter CTR1 in Ovary Cancer. PLoS One. 2015;10:e0125402.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 42]  [Cited by in F6Publishing: 50]  [Article Influence: 5.6]  [Reference Citation Analysis (0)]
81.  Brewer GJ, Dick RD, Johnson V, Wang Y, Yuzbasiyan-Gurkan V, Kluin K, Fink JK, Aisen A. Treatment of Wilson’s disease with ammonium tetrathiomolybdate. I. Initial therapy in 17 neurologically affected patients. Arch Neurol. 1994;51:545-554.  [PubMed]  [DOI]  [Cited in This Article: ]
82.  Mills CF, El-Gallad TT, Bremner I. Effects of molybdate, sulfide, and tetrathiomolybdate on copper metabolism in rats. J Inorg Biochem. 1981;14:189-207.  [PubMed]  [DOI]  [Cited in This Article: ]
83.  MIlls CF, El-Gallad TT, Bremner I, Weham G. Copper and molybdenum absorption by rats given ammonium tetrathiomolybdate. J Inorg Biochem. 1981;14:163-175.  [PubMed]  [DOI]  [Cited in This Article: ]
84.  Chen SJ, Kuo CC, Pan HY, Tsou TC, Yeh SC, Chang JY. Mechanistic basis of a combination D-penicillamine and platinum drugs synergistically inhibits tumor growth in oxaliplatin-resistant human cervical cancer cells in vitro and in vivo. Biochem Pharmacol. 2015;95:28-37.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 20]  [Cited by in F6Publishing: 26]  [Article Influence: 2.9]  [Reference Citation Analysis (0)]
85.  Fu S, Naing A, Fu C, Kuo MT, Kurzrock R. Overcoming platinum resistance through the use of a copper-lowering agent. Mol Cancer Ther. 2012;11:1221-1225.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 53]  [Cited by in F6Publishing: 54]  [Article Influence: 4.5]  [Reference Citation Analysis (0)]