Document Detail


A role for the copper transporter Ctr1 in the synergistic interaction between hyperthermia and cisplatin treatment.
MedLine Citation:
PMID:  23879689     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: Hyperthermia enhances cytotoxic effects of chemotherapeutic agents such as cisplatin. However, the underlying molecular mechanisms remain unclear. We hypothesised that hyperthermia increases cisplatin accumulation and efficacy by modulating function of copper transport protein 1 (Ctr1), a major regulator of cellular cisplatin uptake. We examined the significance of Ctr1 in the synergistic interaction between hyperthermia and cisplatin. We assessed the importance of cisplatin- and hyperthermia-induced Ctr1 multimerisation in sensitising cells to cisplatin cytotoxicity.
MATERIALS AND METHODS: Ctr1 protein levels and cisplatin sensitivities were assessed in bladder cancer cell lines with immunoblotting and clonogenic survival assays. Using Myc-tagged-Ctr1 HEK293 cells, we assessed the effect of hyperthermia on Ctr1 multimerisation with immunoblotting. The effect of hyperthermia on cisplatin sensitivity and accumulation was assessed in wild-type (WT) and Ctr1 knockout (Ctr1-/-) mouse embryonic fibroblasts (MEFs) with clonogenic assays and inductively coupled plasma-mass spectrometry (ICP-MS).
RESULTS: Increased Ctr1 protein expression was observed for the most cisplatin-sensitive bladder cancer cell lines and MEFs. Heat-induced increase in Ctr1 multimerisation with cisplatin was observed in Myc-tagged Ctr1 cells. Hyperthermia enhanced cisplatin-mediated cytotoxicity in WT more than Ctr1-/- cells (dose modifying factors 1.75 versus 1.4, respectively). WT cells accumulated more platinum versus Ctr1-/- cells; this was further increased by hyperthermia in WT cells.
CONCLUSIONS: Hyperthermia enhanced cisplatin uptake and cytotoxicity in WT cells. Heat increased Ctr1 activity by increasing multimerisation, enhancing drug cytotoxicity. Furthermore, Ctr1 protein profiles of bladder tumours, as well as other tumour types, may predict their response to cisplatin and overall efficacy of treatment.
Authors:
Chelsea D Landon; Sarah E Benjamin; Kathleen A Ashcraft; Mark W Dewhirst
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-07-23
Journal Detail:
Title:  International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group     Volume:  29     ISSN:  1464-5157     ISO Abbreviation:  Int J Hyperthermia     Publication Date:  2013 Sep 
Date Detail:
Created Date:  2013-08-20     Completed Date:  2014-03-11     Revised Date:  2014-09-02    
Medline Journal Info:
Nlm Unique ID:  8508395     Medline TA:  Int J Hyperthermia     Country:  England    
Other Details:
Languages:  eng     Pagination:  528-38     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents / administration & dosage*
Cation Transport Proteins / genetics,  metabolism*
Cell Line
Cell Line, Tumor
Cell Survival / drug effects
Cisplatin / administration & dosage*
Fibroblasts / metabolism
HEK293 Cells
Humans
Hyperthermia, Induced*
Mice
RNA, Messenger / metabolism
Urinary Bladder Neoplasms / metabolism*,  therapy
Grant Support
ID/Acronym/Agency:
1F31 AT006644-01/AT/NCCAM NIH HHS; CA42745/CA/NCI NIH HHS; P01 CA042745/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Cation Transport Proteins; 0/RNA, Messenger; 0/copper transporter 1; Q20Q21Q62J/Cisplatin
Comments/Corrections

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