Glutathione modulators reverse the pro-tumour effect of growth factors enhancing WiDr cell response to chemotherapeutic agents.
BACKGROUND
Glutathione has been implicated in growth factor-mediated chemoresistance of colon cancer cells.


METHODS
We evaluated the influence of hepatocyte growth factor, vascular endothelial growth factor and epidermal growth factor on the effect of 5-fluorouracil, oxaliplatin and SN-38 (the active metabolite of irinotecan) on WiDr cells. We also analysed the effect of glutathione modulators (L-buthionine-SR-sulfoximine, and L-2-oxothiazolidine-4-carboxylate) on the growth-promoting effect induced by growth factors and on the antiproliferative activity of the aforementioned drugs.


RESULTS
Exposure to growth factors reduced drug cytotoxic activity, specially in the case of 5-fluorouracil. The addition of L-buthionine-SR-sulfoximine or L-2-oxothiazolidine-4-carboxylate to the chemotherapeutic agents abrogated pro-tumour effects of the growth factors, and produced a greater antitumour activity than the drugs alone.


CONCLUSIONS
Among the combinations analysed, the addition of L-2-oxothiazolidine-4-carboxylate to SN-38 was found to be the best chemotherapeutic combination, resulting in a near 70% increase in the cytotoxic activity of SN-38.
Department of Surgery, Radiology and Physical Medicine, School of Medicine and Dentistry, University of the Basque Country, Leioa, Vizcaya, Spain.
Marta
M
Caramés
Ana
A
Alonso-Varona
Ignacio
I
García-Alonso
Teodoro
T
Palomares
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D019328:Buthionine Sulfoximine / Q000008:administration & dosage / Q000494:pharmacology*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004357:Drug Synergism; D004815:Epidermal Growth Factor; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D017228:Hepatocyte Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D000077146:Irinotecan; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000494:pharmacology; D000077150:Oxaliplatin; D011761:Pyrrolidonecarboxylic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D053778:Thiazolidines / Q000008:administration & dosage / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A
D036341:Intercellular Signaling Peptides and Proteins; D009944:Organoplatinum Compounds; D053778:Thiazolidines; D042461:Vascular Endothelial Growth Factor A; D000077150:Oxaliplatin; D019328:Buthionine Sulfoximine; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D000077146:Irinotecan; D005978:Glutathione; D011761:Pyrrolidonecarboxylic Acid; D005472:Fluorouracil; C029536:2-oxothiazolidine-4-carboxylic acid; D002166:Camptothecin