Rocha Clarissa Ribeiro Reily, Kajitani Gustavo Satoru, Quinet Annabel, Fortunato Rodrigo Soares, Menck Carlos Frederico Martins
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Oncotarget. 2016 Jul 26;7(30):48081-48092. doi: 10.18632/oncotarget.10129.
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.
癌症是全球主要的死亡原因之一，尽管在化疗方面取得了巨大进展，尤其是在化疗领域，但许多类型的癌症预后仍然不佳。就胶质瘤而言，替莫唑胺（TMZ）是主要的治疗选择，但由于耐药性，其治疗效果有限。虽然这种耐药性通常与DNA修复机制有关，但在这项研究中，我们证明氧化应激起着重要作用。我们发现，在TMZ治疗后，核因子红细胞2相关因子2（NRF2）被诱导，它是人类细胞中主要的抗氧化转录因子调节因子。这伴随着肿瘤细胞中谷胱甘肽（GSH）浓度的增加。通过沉默NFR2证明了该途径的有效性，这在体外和体内都大大增强了TMZ治疗后的细胞死亡。此外，将BSO（一种GSH抑制剂）与TMZ联合使用时，观察到更高的DNA损伤和诱导的细胞死亡。在黑色素瘤的体外和体内模型中也观察到了类似的效果，因此可能表明GSH在更广泛的肿瘤中对TMZ耐药性起决定性作用。因此，BSO和TMZ的联合方案构成了一种有趣的治疗选择，可用于对抗胶质瘤和黑色素瘤。
