NRF2 signaling drives chemoresistance in NSCLC and glioblastoma.
de Souza Izadora, Monteiro Linda Karolynne Seregni, da Silva Teixeira Ana Beatriz, Guedes Camila Banca, Lima Karoline Almeida, de Souza Filho Cláudio Henrique Dahne, de Andrade Izabela Amélia Marques, Ramalho Maria Carolina Clares, de Oliveira Beatriz Silva, Lazarini Mariana, Rocha Clarissa Ribeiro Reily
Abstract
Although great advances have been made in cancer treatment, lung cancer and glioblastoma patients continue to present a dismal prognosis, mainly due to drug resistance. Evidence suggests that NRF2 and glutathione (GSH) play a fundamental role in chemotherapy resistance. Notably, GSH depletion by buthionine sulfoximine (BSO) has been demonstrated to sensitize human tumor cells to a wide variety of chemotherapeutic agents. However, the incorporation of BSO into standard chemotherapy regimens lacks a robust clinical rationale. In this study, we aimed to investigate the mechanisms governing differential sensitivity to chemotherapy in lung cancer and glioblastoma cells to identify novel strategies to enhance outcomes in these malignancies. For this purpose, we analyzed several cellular responses in cell lines exhibiting distinct sensitivities to temozolomide (TMZ) and cisplatin. Our findings indicate that the NRF2/GSH pathway plays a crucial role in TMZ and cisplatin resistance and that pharmacological GSH depletion enhances the sensitivity of NRF2-high, chemotherapy-resistant cells to these agents. Furthermore, BSO in combination with TMZ or cisplatin enhanced chemotherapy-induced cytotoxicity and engaged both apoptotic and ferroptosis-related responses in NSCLC cells. These findings provide preclinical evidence supporting further investigation of NRF2/GSH targeting as a strategy to overcome chemotherapy resistance.
Key Findings
- The NRF2/GSH pathway plays a crucial role in temozolomide (TMZ) and cisplatin resistance in NSCLC and glioblastoma cells.
- Pharmacological depletion of glutathione (GSH) using buthionine sulfoximine (BSO) enhances sensitivity of NRF2-high, chemotherapy-resistant cells to TMZ and cisplatin.
- Combination of BSO with TMZ or cisplatin increases chemotherapy-induced cytotoxicity and activates both apoptotic and ferroptosis-related cell death pathways in NSCLC cells.
Clinical Significance
Targeting the NRF2/GSH pathway, particularly through GSH depletion, represents a promising strategy to overcome chemotherapy resistance in lung cancer and glioblastoma, potentially improving treatment outcomes.
Citation
de Souza Izadora, Monteiro Linda Karolynne Seregni, da Silva Teixeira Ana Beatrizet al.. NRF2 signaling drives chemoresistance in NSCLC and glioblastoma. Molecular and cellular biochemistry. 2026-Sep-19.