RESUMEN
Cancer is a leading cause of death worldwide, and while great advances have been made particularly in chemotherapy, many types of cancer still present a dismal prognosis. In the case of glioma, temozolomide (TMZ) is the main option for treatment, but it has limited success due to drug resistance. While this resistance is usually associated to DNA repair mechanisms, in this work we demonstrate that oxidative stress plays an important role. We showed that upon TMZ treatment there is an induction of the nuclear factor erythroid 2-related factor 2 (NRF2), which is the main antioxidant transcription factor regulator in human cells. This is accompanied by an enhancement of glutathione (GSH) concentration in the tumor cells. The effectiveness of this pathway was proven by silencing NFR2, which greatly enhanced cell death upon TMZ treatment both in vitro and in vivo. Also, higher DNA damage and induced cell death was observed by combining BSO - a GSH inhibitor - with TMZ. Similar effects were also observed using in vitro and in vivo models of melanoma, thus possibly indicating that GSH has a decisive role in TMZ resistance in a wider range of tumors. Thus, a combined regimen of BSO and TMZ configures an interesting therapeutic alternative for fighting both glioma and melanoma.
Asunto(s)
Antineoplásicos Alquilantes/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Dacarbazina/análogos & derivados , Glioma/tratamiento farmacológico , Glutatión/metabolismo , Melanoma/tratamiento farmacológico , Factor 2 Relacionado con NF-E2/metabolismo , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Butionina Sulfoximina/administración & dosificación , Línea Celular Tumoral , Dacarbazina/administración & dosificación , Dacarbazina/farmacología , Resistencia a Antineoplásicos , Femenino , Glioma/metabolismo , Glioma/patología , Humanos , Melanoma/metabolismo , Melanoma/patología , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Temozolomida , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The susceptibility of intestinal alkaline phosphatase to DL-buthionine-S,R-sulfoximine was investigated in chicks fed a commercial diet. The results show that DL-buthionine-S,R-sulfoximine produced inhibition of intestinal alkaline phosphatase activity. This effect showed dose- and time-dependency and it was caused by either in vivo DL-buthionine-S,R- sulfoximine administration or in vitro DL-buthionine-S,R-sulfoximine incubation with villus tip enterocytes. DL-Buthionine-S,R-sulfoximine did not act directly on intestinal alkaline phosphatase but it provoked glutathione depletion which led to changes in the redox state of the enterocyte as shown by the production of free hydroxyl radicals and an incremental increase in the carbonyl content of proteins. The reversibility of the buthionine sulfoximine effect on intestinal alkaline phosphatase was proved by addition of glutathione monoester to the duodenal loop.