Abstract/Details

Effects of polyunsaturated fatty acids on multidrug resistance and DNA methylation in human cancer cell lines


2009 2009

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Abstract (summary)

Accumulating evidences indicate that dietary intake of long-chain polyunsaturated fatty acids (PUFAs) can affect various cellular processes and improve response of cancer cells to chemotherapy. The mechanisms by which PUFAs affect this response are not well understood. P-glycoprotein (P-gp), encoded by the multidrug resistance gene MDR1, is a drug efflux transporter that plays an important role in the bioavailability of anti-cancer drugs. Effects of long-chain polyunsaturated fatty acids on MDR1 gene expression and functional activity in the human colon cancer cell line Caco-2 were studied in this research. Caco-2 cells were treated with different concentrations of three PUFAs: eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and arachidonic acid (AA). All three PUFAs down-regulated the expression of the MDR1 gene (EPA, 34%, DHA, 32% and AA, 27%). The inhibition of gene expression by these PUFAs was accompanied by reduction in protein levels of P-gp. The calcein-AM efflux assay indicated that EPA, DHA, and AA can increase intracellular accumulation (hence decrease the efflux) of calcein-AM (a P-gp substrate) by 25% to 31%. In addition, incubation of cells with PUFAs greatly enhanced the cytotoxicity of the anti-cancer drug paclitaxel. All three PUFAs also induced apoptosis and enhanced paclitaxel-induced apoptosis in Caco-2 cells. Together, these results suggest that inhibition of the multidrug resistance MDR1/P-gp is one mechanism through which dietary polyunsaturated fatty acids exert a positive effect on the response of tumor cells to anti-cancer drugs. In addition, transcriptional promotion of the nuclear receptors CAR and PXR by PUFAs was also observed in this study.

Moreover, to determine whether the eicosapentaenoic acid affects BRCA1 expression through promoter methylation, BRCA1 promoter methylation patterns and gene expression in U937 cells were examined. The methylation status of the BRCA1 promoter was evaluated by methylation-specific PCR (MSP) of bisulfite conversion products. The results indicate that methylation of BRCA1 promoter DNA is reduced in EPA-treated cells. The reduction of methylation in the BRCA1 promoter was accompanied by an increase in mRNA levels obtained by real-time quantitative PCR (qPCR), suggesting that DNA methylation is a possible mechanism by which the dietary ω-3 polyunsaturated fatty acids mediate gene expression in human cells.

Because of these characteristics, use of PUFAs as adjuvants presents a promising strategy in cancer prevention and therapeutics.

Indexing (details)


Subject
Pharmacology;
Biomedical engineering
Classification
0419: Pharmacology
0541: Biomedical engineering
Identifier / keyword
Health and environmental sciences; Applied sciences; BRCA1; DNA methylation; Multidrug resistance; Polyunsaturated fatty acids
Title
Effects of polyunsaturated fatty acids on multidrug resistance and DNA methylation in human cancer cell lines
Author
Kuan, Cheng-Yi
Number of pages
149
Publication year
2009
Degree date
2009
School code
0050
Source
DAI-B 70/08, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9781109311983
Advisor
Walker, Terry H.
Committee member
Chen, Chin-Fu; Luo, June; Nghiem, Nhuan
University/institution
Clemson University
Department
Biosystems Engineering
University location
United States -- South Carolina
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3369264
ProQuest document ID
304864276
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/304864276
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