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Carotenoids reverse multidrug resistance in cancer cells by interfering with ABC-transporters.
MedLine Citation:
PMID:  22770743     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Proteins of the ATP-binding cassette superfamily, mainly P-glycoprotein (P-gp; MDR1), play an important role in the development of multidrug resistance (MDR) in cancer cells and thus in the potential failure of chemotherapy. A selection of carotenoids (β-carotene, crocin, retinoic acid, canthaxanthin, and fucoxanthin) was investigated whether they are substrates of P-gp, and if they can reverse MDR in resistant Caco-2 and CEM/ADR5000 cells as compared to the sensitive parent cell line CCRF-CEM. The activity of ABC transporter was determined in resistant and sensitive cells by spectrofluorometry and flow cytometry using the substrates doxorubicin, rhodamine 123, and calcein as fluorescent probes. The carotenoids increased accumulation of these P-gp substrates in a dose-dependent manner indicating that they themselves also function as substrates. Fucoxanthin and canthaxanthin (50-100μM) produced a 3-5-fold higher retention of the fluorescent probes than the known competitive inhibitor verapamil. Carotenoids showed a low cytotoxicity in cells with MDR with IC(50) values between 100 and 200μM. The combination of carotenoids with eight structurally different cytotoxic agents synergistically enhanced their cytotoxicity in Caco-2 cells, probably by inhibiting the function of the ABC transporters. For example, fucoxanthin synergistically enhanced the cytotoxicity of 5-FU 53.37-fold, of vinblastine 51.01-fold, and of etoposide 12.47-fold. RT-PCR was applied to evaluate the mRNA levels of P-gp in Caco-2 cells after treatment with carotenoids. Fucoxanthin and canthaxanthin significantly decreased P-gp levels to 12% and 24%, respectively as compared to untreated control levels (p<0.001). This study implies that carotenoids may be utilised as chemosensitisers, especially as adjuvants in chemotherapy.
Authors:
Safaa Yehia Eid; Mahmoud Zaki El-Readi; Michael Wink
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-7-4
Journal Detail:
Title:  Phytomedicine : international journal of phytotherapy and phytopharmacology     Volume:  -     ISSN:  1618-095X     ISO Abbreviation:  -     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-7-9     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9438794     Medline TA:  Phytomedicine     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 Elsevier GmbH. All rights reserved.
Affiliation:
Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, ImNeuenheimer Feld 364, 69120 Heidelberg, Germany.
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