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

Chen, Helen H.W.; Yan, Jiang; Chen, Wen Chung; Kuo, M. Tien; Lai, Yi-Chun; Lai, Wu‐Wei; Liu, Hsiao Sheng; Su, Wu Chou

doi:10.1016/j.lungcan.2011.06.011

Cited by 73 publications

(56 citation statements)

References 31 publications

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“…The same correlation was seen with human CTR1 (hCTR1) in some tumor cells (Song et al, 2004;Zisowsky et al, 2007). Several subsequent studies confirmed this correlation and led to the suggestion that hCTR1, the major high-affinity copper transporter, also mediates platinum drug uptake (Pabla et al, 2009;Larson et al, 2009Larson et al, , 2010bChen et al, 2012;Kalayda et al, 2012).…”

Section: Introductionmentioning

confidence: 71%

A Re-Evaluation of the Role of hCTR1, the Human High-Affinity Copper Transporter, in Platinum-Drug Entry into Human Cells

Ivy

Kaplan

2013

Mol Pharmacol

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Cisplatin (cDDP) is an anticancer drug used in a number of malignancies, including testicular, ovarian, cervical, bladder, lung, head, and neck cancers. Its use is limited by the development of resistance, often rationalized via effects on cellular uptake. It has been claimed that human copper transporter 1 (hCTR1), the human high-affinity copper transporter, is the major entry pathway for cDDP and related drugs via a mechanism that mimics copper. This is an unexpected property of hCTR1, a highly selective copper (I) transporter. We compared the uptake rates of copper with cDDP (and several analogs) into human embryonic kidney 293 cells overexpressing wildtype or mutant hCTR1, mouse embryonic fibroblasts that do or do not express CTR1, and human ovarian tumor cells that are sensitive or resistant to cDDP. We have also compared the effects of extracellular copper, which causes regulatory endocytosis of hCTR1, to those of cDDP. We confirm the correlation between higher hCTR1 levels and higher platinum drug uptake in tumor cells sensitive to the drug. However, we show that hCTR1 is not the major entry route of platinum drugs, and that the copper transporter is not internalized in response to extracellular drug. Our data suggest the major entry pathway for platinum drugs is not saturable at relevant concentrations and not protein-mediated. Clinical trials have been initiated that depend upon regulating membrane levels of hCTR1. If reduced drug uptake is a major factor in resistance, hCTR1 is unlikely to be a productive target in attempts to enhance efficacy, although the proteins involved in copper homeostasis may play a role.

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Section: Introductionmentioning

confidence: 71%

A Re-Evaluation of the Role of hCTR1, the Human High-Affinity Copper Transporter, in Platinum-Drug Entry into Human Cells

Ivy

Kaplan

2013

Mol Pharmacol

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“…A previous study has reported that hCtr1 expression is able to predict the prognosis of patients with advanced NSCLC that received platinum-based chemotherapy (16). Thus, in the present study, the expression of hCtr1, ATP7A and ATP7B proteins was detected in surgically resected NSCLC tissues to determine the association between the expression of these proteins with the histology, chemotherapy response, tumor stage, differentiation and prognosis in patients with resected NSCLC that received platinum-based treatment.…”

Section: Introductionmentioning

confidence: 86%

“…Ctr1 controls copper uptake, while ATP7A and ATP7B control the copper export from cells (23)(24)(25). Previous studies have identified that copper ion transport proteins are closely associated with the development of cisplatin resistance (16,26,27). These copper transporters include Ctr1 and ATP7B and ATP7A (23,28), which together regulate the overall intracellular cisplatin levels.…”

Section: A B Cmentioning

confidence: 99%

Expression of the copper transporters hCtr1, ATP7A and ATP7B is associated with the response to chemotherapy and survival time in patients with resected non-small cell lung cancer

Tian

Chen

et al. 2015

Oncology Letters

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Abstract.Copper transporter family proteins may regulate the chemoresistance of non-small cell lung cancer (NSCLC) to platinum-based anticancer drugs. The present study aimed to investigate the expression of these proteins in lung cancer tissue specimens for association with clinicopathological data and patient responses to chemotherapy and survival. A total of 54 patients with surgically resected NSCLC that received first-line platinum-based doublet chemotherapy were recruited in the present study, and the paraffin-embedded pre-treatment tumor tissue specimens were subjected to immunohistochemical analysis for the expression of human copper transporter 1 (hCtr1) and copper-transporting p-type adenosine triphosphatase 1 (ATP7A) and 2 (ATP7B). This cohort of patients with NSCLC received platinum-based chemotherapy subsequent to the surgical removal of tumor lesions. ATP7B expression was found to be significantly associated with tumor cell differentiation, while hCtr1 expression was significantly associated with improved chemotherapeutic responses. The median survival time was 20 months in patients possessing tumors with high ATP7A expression, but >66 months in patients possessing tumors with low ATP7A expression at the end of the follow-up (P<0.001). The median survival time at the end of the follow-up was 15 months in patients with low tumor hCtr1 expression, but >66 months in patients with high tumor hCtr1 expression (P<0.001). High hCtr1 and low ATP7A expression were each favorable prognostic factors subsequent to chemotherapy for patients with resected NSCLC. Multivariate analysis revealed that high hCtr1 expression combined with low ATP7A expression, good tumor differentiation and female gender were all favorable independent predictive and prognostic factors for patients with resected NSCLC following chemotherapy. High hCtr1 expression combined with low ATP7A expression was associated with an improved prognosis in patients with resected NSCLC that received platinum-based chemotherapy. Surgery combined with neoadjuvant chemotherapy may improve the survival time of patients with NSCLC.

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“…32 However, in clinical NSCLC specimens, only the copper uptake transporter CTR1, but not ATP7A or ATP7B, predicted clinical outcome after platinum-based chemotherapy. 33 In addition, the observation that NSCLC dose-response curves flatten at higher platinum dose-intensities 34 would be more in keeping with resistance being related to reduced uptake rather than increased efflux. 35 Validating functions of transport factors in NSCLC and incorporating them as biomarkers for platinum sensitivity into future clinical trials would be of significant clinical value.…”

Section: Platinum Concentration and Clinical Outcome In Nsclcmentioning

confidence: 99%

Tissue Platinum Concentration and Tumor Response in Non–Small-Cell Lung Cancer

Kim

Lee

et al. 2012

JCO

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A B S T R A C T PurposePlatinum resistance is a major limitation in the treatment of advanced non-small-cell lung cancer (NSCLC). Reduced intracellular drug accumulation is one of the most consistently identified features of platinum-resistant cell lines, but clinical data are limited. We assessed the effects of tissue platinum concentrations on response and survival in NSCLC. Patients and MethodsWe measured total platinum concentrations by flameless atomic absorption spectrophotometry in 44 archived fresh-frozen NSCLC specimens from patients who underwent surgical resection after neoadjuvant platinum-based chemotherapy. Tissue platinum concentration was correlated with percent reduction in tumor size on post-versus prechemotherapy computed tomography scans. The relationship between tissue platinum concentration and survival was assessed by univariate and multicovariate Cox proportional hazards regression model analysis and Kaplan-Meier analysis. ResultsTissue platinum concentration correlated significantly with percent reduction in tumor size (P Ͻ .001). The same correlations were seen with cisplatin, carboplatin, and all histology subgroups. Furthermore, there was no significant impact of potential variables such as number of cycles and time lapse from last chemotherapy on platinum concentration. Patients with higher platinum concentration had longer time to recurrence (P ϭ .034), progression-free survival (P ϭ .018), and overall survival (P ϭ .005) in the multicovariate Cox model analysis after adjusting for number of cycles. ConclusionThis clinical study established a relationship between tissue platinum concentration and response in NSCLC. It suggests that reduced platinum accumulation might be an important mechanism of platinum resistance in the clinical setting. Further studies investigating factors that modulate intracellular platinum concentration are warranted.

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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

Cited by 73 publications

References 31 publications

A Re-Evaluation of the Role of hCTR1, the Human High-Affinity Copper Transporter, in Platinum-Drug Entry into Human Cells

A Re-Evaluation of the Role of hCTR1, the Human High-Affinity Copper Transporter, in Platinum-Drug Entry into Human Cells

Expression of the copper transporters hCtr1, ATP7A and ATP7B is associated with the response to chemotherapy and survival time in patients with resected non-small cell lung cancer

Tissue Platinum Concentration and Tumor Response in Non–Small-Cell Lung Cancer

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