Abstract
Curcumin, a constituent of turmeric, has anti-inflammatory, anti-carcinogenic, and chemopreventive effects in several animal tumor models. The expression of P-glycoprotein (P-gp), encoded by the mdr gene, is often associated with multidrug resistance (MDR) to unrelated chemotherapeutic drugs in cancer cells. Here, we demonstrate that curcumin down-regulates P-gp expression in multidrug-resistant L1210/Adr cells. Transfection with a series of 5'-deleted constructs of the mdr1b gene promoter indicated that a proximal region between -205 and +42 of the sequence was responsible for the suppression of promoter activity by curcumin. This response might be associated with the inhibition of the phosphatidyinositol 3-kinase (PI3K)/Akt/nuclear factor-kappa B (NF-kappa B) signaling pathway by curcumin. Moreover, curcumin reversed the MDR of the L1210/Adr cells. Thus, curcumin can contribute to the reversal of the MDR phenotype, probably due to the suppression of P-gp expression via the inhibition of the PI3K/Akt/NF-kappa B signaling pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B / genetics
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ATP Binding Cassette Transporter, Subfamily B / metabolism*
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ATP-Binding Cassette Sub-Family B Member 4
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Animals
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Antibiotics, Antineoplastic / pharmacology
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Antineoplastic Agents, Phytogenic / pharmacology*
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Antineoplastic Agents, Phytogenic / therapeutic use
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Cell Line, Tumor
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Curcumin / pharmacology*
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Curcumin / therapeutic use
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Dose-Response Relationship, Drug
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Down-Regulation
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Doxorubicin / pharmacology
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Drug Resistance, Multiple / drug effects
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Drug Resistance, Neoplasm / drug effects
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Gene Expression Regulation, Neoplastic / drug effects
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Leukemia L1210 / drug therapy*
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Leukemia L1210 / enzymology
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Leukemia L1210 / metabolism
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Mice
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism*
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NIH 3T3 Cells
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphoinositide-3 Kinase Inhibitors
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Promoter Regions, Genetic / drug effects
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / therapeutic use
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Proto-Oncogene Proteins c-akt / metabolism*
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Sequence Deletion
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Signal Transduction / drug effects
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Transcription, Genetic / drug effects
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Transfection
Substances
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ATP Binding Cassette Transporter, Subfamily B
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Antibiotics, Antineoplastic
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Antineoplastic Agents, Phytogenic
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NF-kappa B
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Doxorubicin
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Proto-Oncogene Proteins c-akt
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Curcumin