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.
Materials and 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.
Conclusion: GSH manipulation could yield a therapeutic gain for chemotherapy with 5-FU in the presence of GFs.