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

Autor: Ruth Croxford, S. E. Kim, Peter D. Cole, Robert C. Cho, Anna Ly, L. Ishiguro, Kyoung-Jin Sohn, Young-In Kim, Barton A. Kamen
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Male
Cancer Research
Colorectal cancer
medicine.medical_treatment
chemotherapy
Mice
0302 clinical medicine
Antineoplastic Combined Chemotherapy Protocols
5-fluorouracil
RNA
Small Interfering
0303 health sciences
Mice
Inbred BALB C
Oncology
Biochemistry
colon cancer
Fluorouracil
030220 oncology & carcinogenesis
Colonic Neoplasms
Female
medicine.drug
Mice
Nude
Breast Neoplasms
Biology
Adenocarcinoma
folate
Transfection
methotrexate
03 medical and health sciences
Breast cancer
breast cancer
Folic Acid
Cell Line
Tumor
Hydrolase
medicine
Animals
Humans
030304 developmental biology
γ-glutamyl hydrolase
Chemotherapy
gamma-Glutamyl Hydrolase
medicine.disease
HCT116 Cells
Xenograft Model Antitumor Assays
digestive system diseases
γ glutamyl hydrolase
Cancer cell
Cancer research
Methotrexate
Drug Screening Assays
Antitumor
Translational Therapeutics
Zdroj: British Journal of Cancer
ISSN: 1532-1827
0007-0920
Popis: 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.
Databáze: OpenAIRE
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