Glutathione modulation reverses the growth-promoting effect of growth factors, improving the 5-fluorouracil antitumour response in WiDr colon cancer cells.
BACKGROUND
A common cause of treatment failure in colorectal cancer is chemoresistance, which may be related to the redox state of cancer cells and the tumour microenvironment, where growth factors (GFs) play an important role. Glutathione (GSH), a key regulator of the redox balance, is involved in GF signalling systems and may also protect against drug-induced cellular injury.


METHODS
The effect of GSH modulation on 5-fluorouracil (5-FU) activity on the WiDr colon cancer cell line was studied. Cell proliferation and GSH content were assessed. Cells were exposed to the GSH modulators, L-buthionine-SR-sulfoximine (BSO) or L 2 oxothiazolidine-4-carboxylate (OTZ), before treatment with 5-FU in the presence of hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) or epidermal growth factor (EGF).


RESULTS
Exposure to GFs significantly increased GSH levels and induced a pro-tumour effect. During the first 48 h of incubation, VEGF and EGF induced a near 30% reduction in 5-FU antitumour activity, while exposure to HGF abrogated the drug-induced growth inhibition. Treatment with OTZ and BSO abrogated the growth-promoting effects of GFs. Moreover, the addition of either of the GSH modulators to 5-FU produced an increase of nearly 40% in the 5-FU activity in the case of HGF or VEGF, and a 25% increase in the case of EGF.


CONCLUSIONS
GSH manipulation could yield a therapeutic gain for chemotherapy with 5-FU in the presence of GFs.
Department of Surgery, School of Medicine and Dentistry, University of the Basque Country, Leioa, E-48940 Vizcaya, Spain. teodoro.palomares@ehu.es
Teodoro
T
Palomares
Marta
M
Caramés
Ignacio
I
García-Alonso
Ana
A
Alonso-Varona
D019328:Buthionine Sulfoximine / Q000494:pharmacology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D011761:Pyrrolidonecarboxylic Acid / Q000494:pharmacology; D053778:Thiazolidines / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D036341:Intercellular Signaling Peptides and Proteins; D053778:Thiazolidines; D042461:Vascular Endothelial Growth Factor A; D019328:Buthionine Sulfoximine; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D005978:Glutathione; D011761:Pyrrolidonecarboxylic Acid; D005472:Fluorouracil; C029536:2-oxothiazolidine-4-carboxylic acid