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In vivo [(64)Cu]CuCl(2) PET imaging reveals activity of Dextran-Catechin on tumor copper homeostasis

Given the strong clinical evidence that copper levels are significantly elevated in a wide spectrum of tumors, copper homeostasis is considered as an emerging target for anticancer drug design. Monitoring copper levels in vivo is therefore of paramount importance when assessing the efficacy of coppe...

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Autores principales: Parmar, Arvind, Pascali, Giancarlo, Voli, Florida, Lerra, Luigi, Yee, Eugene, Ahmed-Cox, Aria, Kimpton, Kathleen, Cirillo, Giuseppe, Arthur, Andrew, Zahra, David, Rahardjo, Gita, Liu, Guo Jun, Lengkeek, Nigel, Saletta, Federica, Charil, Arnaud, Kavallaris, Maria, Vittorio, Orazio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276294/
https://www.ncbi.nlm.nih.gov/pubmed/30555570
http://dx.doi.org/10.7150/thno.29840
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author Parmar, Arvind
Pascali, Giancarlo
Voli, Florida
Lerra, Luigi
Yee, Eugene
Ahmed-Cox, Aria
Kimpton, Kathleen
Cirillo, Giuseppe
Arthur, Andrew
Zahra, David
Rahardjo, Gita
Liu, Guo Jun
Lengkeek, Nigel
Saletta, Federica
Charil, Arnaud
Kavallaris, Maria
Vittorio, Orazio
author_facet Parmar, Arvind
Pascali, Giancarlo
Voli, Florida
Lerra, Luigi
Yee, Eugene
Ahmed-Cox, Aria
Kimpton, Kathleen
Cirillo, Giuseppe
Arthur, Andrew
Zahra, David
Rahardjo, Gita
Liu, Guo Jun
Lengkeek, Nigel
Saletta, Federica
Charil, Arnaud
Kavallaris, Maria
Vittorio, Orazio
author_sort Parmar, Arvind
collection PubMed
description Given the strong clinical evidence that copper levels are significantly elevated in a wide spectrum of tumors, copper homeostasis is considered as an emerging target for anticancer drug design. Monitoring copper levels in vivo is therefore of paramount importance when assessing the efficacy of copper-targeting drugs. Herein, we investigated the activity of the copper-targeting compound Dextran-Catechin by developing a [(64)Cu]CuCl(2) PET imaging protocol to monitor its effect on copper homeostasis in tumors. Methods: Protein expression of copper transporter 1 (CTR1) in tissue microarrays representing 90 neuroblastoma patient tumors was assessed by immunohistochemistry. Western blotting analysis was used to study the effect of Dextran-Catechin on the expression of CTR1 in neuroblastoma cell lines and in tumors. A preclinical human neuroblastoma xenograft model was used to study anticancer activity of Dextran-Catechin in vivo and its effect on tumor copper homeostasis. PET imaging with [(64)Cu]CuCl(2) was performed in such preclinical neuroblastoma model to monitor alteration of copper levels in tumors during treatment. Results: CTR1 protein was found to be highly expressed in patient neuroblastoma tumors by immunohistochemistry. Treatment of neuroblastoma cell lines with Dextran-Catechin resulted in decreased levels of glutathione and in downregulation of CTR1 expression, which caused a significant decrease of intracellular copper. No changes in CTR1 expression was observed in normal human astrocytes after Dextran-Catechin treatment. In vivo studies and PET imaging analysis using the neuroblastoma preclinical model revealed elevated [(64)Cu]CuCl(2) retention in the tumor mass. Following treatment with Dextran-Catechin, there was a significant reduction in radioactive uptake, as well as reduced tumor growth. Ex vivo analysis of tumors collected from Dextran-Catechin treated mice confirmed the reduced levels of CTR1. Interestingly, copper levels in blood were not affected by treatment, demonstrating potential tumor specificity of Dextran-Catechin activity. Conclusion: Dextran-Catechin mediates its activity by lowering CTR1 and intracellular copper levels in tumors. This finding further reveals a potential therapeutic strategy for targeting copper-dependent cancers and presents a novel PET imaging method to assess patient response to copper-targeting anticancer treatments.
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spelling pubmed-62762942018-12-14 In vivo [(64)Cu]CuCl(2) PET imaging reveals activity of Dextran-Catechin on tumor copper homeostasis Parmar, Arvind Pascali, Giancarlo Voli, Florida Lerra, Luigi Yee, Eugene Ahmed-Cox, Aria Kimpton, Kathleen Cirillo, Giuseppe Arthur, Andrew Zahra, David Rahardjo, Gita Liu, Guo Jun Lengkeek, Nigel Saletta, Federica Charil, Arnaud Kavallaris, Maria Vittorio, Orazio Theranostics Research Paper Given the strong clinical evidence that copper levels are significantly elevated in a wide spectrum of tumors, copper homeostasis is considered as an emerging target for anticancer drug design. Monitoring copper levels in vivo is therefore of paramount importance when assessing the efficacy of copper-targeting drugs. Herein, we investigated the activity of the copper-targeting compound Dextran-Catechin by developing a [(64)Cu]CuCl(2) PET imaging protocol to monitor its effect on copper homeostasis in tumors. Methods: Protein expression of copper transporter 1 (CTR1) in tissue microarrays representing 90 neuroblastoma patient tumors was assessed by immunohistochemistry. Western blotting analysis was used to study the effect of Dextran-Catechin on the expression of CTR1 in neuroblastoma cell lines and in tumors. A preclinical human neuroblastoma xenograft model was used to study anticancer activity of Dextran-Catechin in vivo and its effect on tumor copper homeostasis. PET imaging with [(64)Cu]CuCl(2) was performed in such preclinical neuroblastoma model to monitor alteration of copper levels in tumors during treatment. Results: CTR1 protein was found to be highly expressed in patient neuroblastoma tumors by immunohistochemistry. Treatment of neuroblastoma cell lines with Dextran-Catechin resulted in decreased levels of glutathione and in downregulation of CTR1 expression, which caused a significant decrease of intracellular copper. No changes in CTR1 expression was observed in normal human astrocytes after Dextran-Catechin treatment. In vivo studies and PET imaging analysis using the neuroblastoma preclinical model revealed elevated [(64)Cu]CuCl(2) retention in the tumor mass. Following treatment with Dextran-Catechin, there was a significant reduction in radioactive uptake, as well as reduced tumor growth. Ex vivo analysis of tumors collected from Dextran-Catechin treated mice confirmed the reduced levels of CTR1. Interestingly, copper levels in blood were not affected by treatment, demonstrating potential tumor specificity of Dextran-Catechin activity. Conclusion: Dextran-Catechin mediates its activity by lowering CTR1 and intracellular copper levels in tumors. This finding further reveals a potential therapeutic strategy for targeting copper-dependent cancers and presents a novel PET imaging method to assess patient response to copper-targeting anticancer treatments. Ivyspring International Publisher 2018-11-09 /pmc/articles/PMC6276294/ /pubmed/30555570 http://dx.doi.org/10.7150/thno.29840 Text en © Ivyspring International Publisher This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Parmar, Arvind
Pascali, Giancarlo
Voli, Florida
Lerra, Luigi
Yee, Eugene
Ahmed-Cox, Aria
Kimpton, Kathleen
Cirillo, Giuseppe
Arthur, Andrew
Zahra, David
Rahardjo, Gita
Liu, Guo Jun
Lengkeek, Nigel
Saletta, Federica
Charil, Arnaud
Kavallaris, Maria
Vittorio, Orazio
In vivo [(64)Cu]CuCl(2) PET imaging reveals activity of Dextran-Catechin on tumor copper homeostasis
title In vivo [(64)Cu]CuCl(2) PET imaging reveals activity of Dextran-Catechin on tumor copper homeostasis
title_full In vivo [(64)Cu]CuCl(2) PET imaging reveals activity of Dextran-Catechin on tumor copper homeostasis
title_fullStr In vivo [(64)Cu]CuCl(2) PET imaging reveals activity of Dextran-Catechin on tumor copper homeostasis
title_full_unstemmed In vivo [(64)Cu]CuCl(2) PET imaging reveals activity of Dextran-Catechin on tumor copper homeostasis
title_short In vivo [(64)Cu]CuCl(2) PET imaging reveals activity of Dextran-Catechin on tumor copper homeostasis
title_sort in vivo [(64)cu]cucl(2) pet imaging reveals activity of dextran-catechin on tumor copper homeostasis
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276294/
https://www.ncbi.nlm.nih.gov/pubmed/30555570
http://dx.doi.org/10.7150/thno.29840
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