Inhibit multidrug resistance and induce apoptosis by using glycocholic acid and epirubicin.
Cancer-cell resistance to chemotherapy limits the efficacy of cancer treatment. The primary mechanisms of multidrug resistance (MDR) are "pump" and "non-pump" resistance. We evaluated the effects and mechanisms of glycocholic acid (GC), a bile acid, on inhibiting pump and non-pump resistance, and increasing the chemosensitivity of epirubicin in human colon adenocarcinoma Caco-2 cells and rat intestine. GC increased the cytotoxicity of epirubicin, significantly increased the intracellular accumulation of epirubicin in Caco-2 cells and the absorption of epirubicin in rat small intestine, and intensified epirubicin-induced apoptosis. GC and epirubicin significantly reduced mRNA expression levels of human intestinal MDR1, MDR-associated protein (MRP)1, and MRP2; downregulated the MDR1 promoter region; suppressed the mRNA expression of Bcl-2; induced the mRNA expression of Bax; and significantly increased the Bax-to-Bcl-2 ratio and the mRNA levels of p53, caspase-9 and -3. This suggests that GC- and epirubicin-induced apoptosis was mediated through the mitochondrial pathway. We conclude that simultaneous suppression of pump and non-pump resistance dramatically increased the chemosensitivity of epirubicin. A combination of anticancer drugs with GC can control MDR via a mechanism that involves modulating P-gp and MRPs as well as regulating apoptosis-related pathways.
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Department of Biological Sciences and Technology, National University of Tainan, Tainan City 700, Taiwan. yulilo@mail.nutn.edu.tw
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D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects; D002843:Chromatin / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015251:Epirubicin / Q000494:pharmacology*; D005434:Flow Cytometry; D006000:Glycocholic Acid / Q000494:pharmacology*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008156:Luciferases / Q000737:chemistry / Q000378:metabolism; D008297:Male; D008856:Microscopy, Fluorescence; D010957:Plasmids / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D018435:ATP Binding Cassette Transporter, Subfamily B; D000903:Antibiotics, Antineoplastic; D002843:Chromatin; D004273:DNA, Neoplasm; D015251:Epirubicin; D008156:Luciferases; D006000:Glycocholic Acid