Glucuronidation as a mechanism of intrinsic drug resistance in human colon cancer: Reversal of resistance by food additives

Colon cancer exhibits inherent insensitivity to chemotherapy by mechanisms that are poorly characterized. We have shown that human colon cancer cells are efficient in drug conjugation catalyzed by UDP-glucuronosyltransferases (UGTs) and now report on the role of glucuronidation in de novo resistance...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2003-12, Vol.63 (23), p.8443-8450
Main Authors: CUMMINGS, Jeffrey, ETHELL, Brian T, JARDINE, Lesley, BOYD, Gary, MACPHERSON, Janet S, BURCHELL, Brian, SMYTH, John F, JODRELL, Duncan I
Format: Article
Language:English
Subjects:
Anthraquinones - metabolism
Antineoplastic agents
Biological and medical sciences
Biopsy
Camptothecin - analogs & derivatives
Camptothecin - metabolism
Catalysis
Cell Line, Tumor
Colonic Neoplasms - drug therapy
Colonic Neoplasms - enzymology
Colonic Neoplasms - metabolism
Drug Resistance, Neoplasm - drug effects
Enzyme Inhibitors - metabolism
Food Additives - pharmacology
Glucuronides - metabolism
Glucuronosyltransferase - metabolism
Humans
Isoenzymes - metabolism
Medical sciences
Pharmacology. Drug treatments
Propofol - metabolism
Propofol - pharmacology
Topoisomerase I Inhibitors
Tumors
Tyrosine - analogs & derivatives
Tyrosine - metabolism
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Summary:Colon cancer exhibits inherent insensitivity to chemotherapy by mechanisms that are poorly characterized. We have shown that human colon cancer cells are efficient in drug conjugation catalyzed by UDP-glucuronosyltransferases (UGTs) and now report on the role of glucuronidation in de novo resistance to two topoisomerase I inhibitors. Identification of the UGT responsible for glucuronidation of SN-38 and the anthraquinone NU/ICRF 505 was achieved by first using a panel of human cDNA-expressed isozymes to measure conjugating activity. HT29 colon cancer cells were then probed by reverse transcriptase-PCR, Western Blot analysis, and liquid chromatography with mass spectrometry for their profile and activity of UGT isozymes and screened for effective inhibitors of glucuronidation. Expression analysis was also conducted in colon cancer biopsies and paired adjacent normal colon specimens. UGT1A9 was identified as the isozyme catalyzing biotransformation of the two compounds in HT29 cells and propofol as an effective competitive inhibitor of this metabolism. Inhibition of glucuronidation resulted in up to a 5-fold enhancement in drug activity. The majority of colon cancer biopsies studies expressed UGT protein at levels greater than in HT29 cells but with marked interpatient variations and proficiently glucuronidated the two anticancer drugs. A range of UGT aglycones were capable of modulating glucuronidation in the biopies with octylgallate being 10-fold more potent (ID(50) 24 microM) than propofol. In a subset of tumors (33%), UGT protein levels and activity exceeded that of paired normal colon. Glucuronidation may represent a mechanism of intrinsic drug resistance in colon cancer open to modulation by a range of food additives and proprietary medicines.
ISSN:0008-5472
1538-7445