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

Jeffrey Cummings, Brian T. Ethell, Lesley Jardine, Gary Boyd, Janet S. Macpherson, Brian Burchell, John F. Smyth, Duncan I. Jodrell

Research output: Contribution to journalArticle

Abstract

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 cDNAexpressed 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 (ID50 24 M) 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.
Original languageEnglish
Pages (from-to)8443-8450
Number of pages8
JournalCancer Research
Volume63
Issue number23
Publication statusPublished - 1 Dec 2003
Externally publishedYes

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Glucuronosyltransferase
Food Additives
Drug Resistance
Colonic Neoplasms
Isoenzymes
HT29 Cells
irinotecan
Propofol
Colon
Pharmaceutical Preparations
Topoisomerase I Inhibitors
Biopsy
Anthraquinones
Biotransformation
Reverse Transcriptase Polymerase Chain Reaction
Liquid Chromatography
Mass Spectrometry
Proteins
Western Blotting
Drug Therapy

Cite this

Cummings, J., Ethell, B. T., Jardine, L., Boyd, G., Macpherson, J. S., Burchell, B., ... Jodrell, D. I. (2003). Glucuronidation as a mechanism of intrinsic drug resistance in human colon cancer: reversal of resistance by food additives. Cancer Research, 63(23), 8443-8450.
Cummings, Jeffrey ; Ethell, Brian T. ; Jardine, Lesley ; Boyd, Gary ; Macpherson, Janet S. ; Burchell, Brian ; Smyth, John F. ; Jodrell, Duncan I. / Glucuronidation as a mechanism of intrinsic drug resistance in human colon cancer : reversal of resistance by food additives. In: Cancer Research. 2003 ; Vol. 63, No. 23. pp. 8443-8450.
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Cummings, J, Ethell, BT, Jardine, L, Boyd, G, Macpherson, JS, Burchell, B, Smyth, JF & Jodrell, DI 2003, 'Glucuronidation as a mechanism of intrinsic drug resistance in human colon cancer: reversal of resistance by food additives' Cancer Research, vol. 63, no. 23, pp. 8443-8450.

Glucuronidation as a mechanism of intrinsic drug resistance in human colon cancer : reversal of resistance by food additives. / Cummings, Jeffrey; Ethell, Brian T.; Jardine, Lesley; Boyd, Gary; Macpherson, Janet S.; Burchell, Brian; Smyth, John F.; Jodrell, Duncan I.

In: Cancer Research, Vol. 63, No. 23, 01.12.2003, p. 8443-8450.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Glucuronidation as a mechanism of intrinsic drug resistance in human colon cancer

T2 - reversal of resistance by food additives

AU - Cummings, Jeffrey

AU - Ethell, Brian T.

AU - Jardine, Lesley

AU - Boyd, Gary

AU - Macpherson, Janet S.

AU - Burchell, Brian

AU - Smyth, John F.

AU - Jodrell, Duncan I.

PY - 2003/12/1

Y1 - 2003/12/1

N2 - 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 cDNAexpressed 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 modulatingglucuronidation in the biopies with octylgallate being 10-fold more potent (ID50 24 M) 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.

AB - 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 cDNAexpressed 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 modulatingglucuronidation in the biopies with octylgallate being 10-fold more potent (ID50 24 M) 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.

M3 - Article

VL - 63

SP - 8443

EP - 8450

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 23

ER -

Cummings J, Ethell BT, Jardine L, Boyd G, Macpherson JS, Burchell B et al. Glucuronidation as a mechanism of intrinsic drug resistance in human colon cancer: reversal of resistance by food additives. Cancer Research. 2003 Dec 1;63(23):8443-8450.