γ-Glutamyl hydrolase modulation and folate influence chemosensitivity of cancer cells to 5-fluorouracil and methotrexate

S. E. Kim, P. D. Cole, R. C. Cho, A. Ly, L. Ishiguro, K. J. Sohn, R. Croxford, B. A. Kamen, Y. I. Kim

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Background:γ-Glutamyl hydrolase (GGH) regulates intracellular folate and antifolates for optimal nucleotide biosynthesis and antifolate-induced cytotoxicity, respectively. The modulation of GGH may therefore affect chemosensitivity of cancer cells, and exogenous folate levels may further modify this effect.Methods:We generated a novel model of GGH modulation in human HCT116 and MDA-MB-435 cancer cells and investigated the effect of GGH modulation on chemosensitivity to 5-fluorouracil (5FU) and methotrexate (MTX) at different folate concentrations in vitro and in vivo.Results:Overexpression of GGH significantly decreased chemosensitivity of MDA-MB-435 cells to 5FU and MTX at all folate concentrations as expected. In contrast, in HCT116 cells this predicted effect was observed only at very high folate concentration, and as the folate concentration decreased this effect became null or paradoxically increased. This in vitro observation was confirmed in vivo. Inhibition of GGH significantly increased chemosensitivity of both cancer cells to 5FU at all folate concentrations. Unexpectedly, GGH inhibition significantly decreased chemosensitivity of both cancer cells to MTX at all folate concentrations. In both GGH modulation systems and cell lines, the magnitude of chemosensitivity effect incrementally increased as folate concentration increased.Conclusion: Modulation of GGH affects chemosensitivity of cancer cells to 5FU and MTX, and exogenous folate levels can further modify the effects.

Original languageEnglish (US)
Pages (from-to)2175-2188
Number of pages14
JournalBritish Journal of Cancer
Volume109
Issue number8
DOIs
StatePublished - Oct 15 2013

Fingerprint

Hydrolases
Folic Acid
Methotrexate
Fluorouracil
Neoplasms
Folic Acid Antagonists
HCT116 Cells
Nucleotides
Observation
Cell Line

Keywords

  • 5-fluorouracil
  • breast cancer
  • chemotherapy
  • colon cancer
  • folate
  • g-glutamyl hydrolase
  • methotrexate

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

γ-Glutamyl hydrolase modulation and folate influence chemosensitivity of cancer cells to 5-fluorouracil and methotrexate. / Kim, S. E.; Cole, P. D.; Cho, R. C.; Ly, A.; Ishiguro, L.; Sohn, K. J.; Croxford, R.; Kamen, B. A.; Kim, Y. I.

In: British Journal of Cancer, Vol. 109, No. 8, 15.10.2013, p. 2175-2188.

Research output: Contribution to journalArticle

Kim, SE, Cole, PD, Cho, RC, Ly, A, Ishiguro, L, Sohn, KJ, Croxford, R, Kamen, BA & Kim, YI 2013, 'γ-Glutamyl hydrolase modulation and folate influence chemosensitivity of cancer cells to 5-fluorouracil and methotrexate', British Journal of Cancer, vol. 109, no. 8, pp. 2175-2188. https://doi.org/10.1038/bjc.2013.579
Kim, S. E. ; Cole, P. D. ; Cho, R. C. ; Ly, A. ; Ishiguro, L. ; Sohn, K. J. ; Croxford, R. ; Kamen, B. A. ; Kim, Y. I. / γ-Glutamyl hydrolase modulation and folate influence chemosensitivity of cancer cells to 5-fluorouracil and methotrexate. In: British Journal of Cancer. 2013 ; Vol. 109, No. 8. pp. 2175-2188.
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abstract = "Background:γ-Glutamyl hydrolase (GGH) regulates intracellular folate and antifolates for optimal nucleotide biosynthesis and antifolate-induced cytotoxicity, respectively. The modulation of GGH may therefore affect chemosensitivity of cancer cells, and exogenous folate levels may further modify this effect.Methods:We generated a novel model of GGH modulation in human HCT116 and MDA-MB-435 cancer cells and investigated the effect of GGH modulation on chemosensitivity to 5-fluorouracil (5FU) and methotrexate (MTX) at different folate concentrations in vitro and in vivo.Results:Overexpression of GGH significantly decreased chemosensitivity of MDA-MB-435 cells to 5FU and MTX at all folate concentrations as expected. In contrast, in HCT116 cells this predicted effect was observed only at very high folate concentration, and as the folate concentration decreased this effect became null or paradoxically increased. This in vitro observation was confirmed in vivo. Inhibition of GGH significantly increased chemosensitivity of both cancer cells to 5FU at all folate concentrations. Unexpectedly, GGH inhibition significantly decreased chemosensitivity of both cancer cells to MTX at all folate concentrations. In both GGH modulation systems and cell lines, the magnitude of chemosensitivity effect incrementally increased as folate concentration increased.Conclusion: Modulation of GGH affects chemosensitivity of cancer cells to 5FU and MTX, and exogenous folate levels can further modify the effects.",
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AU - Kim, S. E.

AU - Cole, P. D.

AU - Cho, R. C.

AU - Ly, A.

AU - Ishiguro, L.

AU - Sohn, K. J.

AU - Croxford, R.

AU - Kamen, B. A.

AU - Kim, Y. I.

PY - 2013/10/15

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N2 - Background:γ-Glutamyl hydrolase (GGH) regulates intracellular folate and antifolates for optimal nucleotide biosynthesis and antifolate-induced cytotoxicity, respectively. The modulation of GGH may therefore affect chemosensitivity of cancer cells, and exogenous folate levels may further modify this effect.Methods:We generated a novel model of GGH modulation in human HCT116 and MDA-MB-435 cancer cells and investigated the effect of GGH modulation on chemosensitivity to 5-fluorouracil (5FU) and methotrexate (MTX) at different folate concentrations in vitro and in vivo.Results:Overexpression of GGH significantly decreased chemosensitivity of MDA-MB-435 cells to 5FU and MTX at all folate concentrations as expected. In contrast, in HCT116 cells this predicted effect was observed only at very high folate concentration, and as the folate concentration decreased this effect became null or paradoxically increased. This in vitro observation was confirmed in vivo. Inhibition of GGH significantly increased chemosensitivity of both cancer cells to 5FU at all folate concentrations. Unexpectedly, GGH inhibition significantly decreased chemosensitivity of both cancer cells to MTX at all folate concentrations. In both GGH modulation systems and cell lines, the magnitude of chemosensitivity effect incrementally increased as folate concentration increased.Conclusion: Modulation of GGH affects chemosensitivity of cancer cells to 5FU and MTX, and exogenous folate levels can further modify the effects.

AB - Background:γ-Glutamyl hydrolase (GGH) regulates intracellular folate and antifolates for optimal nucleotide biosynthesis and antifolate-induced cytotoxicity, respectively. The modulation of GGH may therefore affect chemosensitivity of cancer cells, and exogenous folate levels may further modify this effect.Methods:We generated a novel model of GGH modulation in human HCT116 and MDA-MB-435 cancer cells and investigated the effect of GGH modulation on chemosensitivity to 5-fluorouracil (5FU) and methotrexate (MTX) at different folate concentrations in vitro and in vivo.Results:Overexpression of GGH significantly decreased chemosensitivity of MDA-MB-435 cells to 5FU and MTX at all folate concentrations as expected. In contrast, in HCT116 cells this predicted effect was observed only at very high folate concentration, and as the folate concentration decreased this effect became null or paradoxically increased. This in vitro observation was confirmed in vivo. Inhibition of GGH significantly increased chemosensitivity of both cancer cells to 5FU at all folate concentrations. Unexpectedly, GGH inhibition significantly decreased chemosensitivity of both cancer cells to MTX at all folate concentrations. In both GGH modulation systems and cell lines, the magnitude of chemosensitivity effect incrementally increased as folate concentration increased.Conclusion: Modulation of GGH affects chemosensitivity of cancer cells to 5FU and MTX, and exogenous folate levels can further modify the effects.

KW - 5-fluorouracil

KW - breast cancer

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KW - g-glutamyl hydrolase

KW - methotrexate

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