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Background: The incidence rate of the esophageal adenocarcinoma (EAC) has increased rapidly among men during the past four decades in the USA and western countries while the 5 year survival rate is still below 20%. Traditional chemotherapy is still the main stream strategy in treatment of EAC patients. However, chemo-resistance usually develops that finally leads to failure of treatments. NFE2-related factor 2 (NRF2) is the master regulator of cellular anti-oxidant properties that maintains cell viability and cellular homeostasis. Overexpression of NRF2 in human cancers are associated with drug-resistance and poor prognosis. Methods and Results: NRF2 protein levels are higher in several EAC cell lines, as compared to BE cell lines (CPA, BAR10T) and normal esophageal squamous cell lines, using Western blot analysis. We confirmed NRF2 overexpression in primary EAC samples, using immunohistochemistry on a tissue microarray that contained 76 EACs. Brusatol is an NRF2 specific inhibitor originated from natural plant. Administration of Brusatol in EAC cells significantly inhibited NRF2 ARE luciferase activity and reduced gene expression of NRF2 target genes such as GR, HO1, GSTM2, GPX3 and GPX4, resulting in a significant increase in cellular ROS levels, which were further increased by treatment with CDDP with subsequent increase in cancer cell death. Further investigation revealed that Brusatol significantly increased lipid peroxidation levels as detected by immunofluorescence assay and flow cytometry and resulted in significant ferroptosis, in particular in combination with CDDP treatments. We confirmed that Brusatol in combination with CDDP significantly suppressed tumor growth in a xenografting mice model. Conclusion: Constitutive overexpression of NRF2 in EAC cells favors tumor cell survival and drug resistance. NRF2 specific inhibitor may synergize with traditional chemotherapeutic drugs by inducing lipid peroxidation and ferroptosis in EAC. Citation Format: Dunfa Peng, Tianling Hu, Lei Chen, Heng Lu, Shoumin Zhu, Wael El-Rifai. Targeting NRF2 using specific inhibitor brusatol sensitized esophageal adenocarcinoma cells to cisplatin through inducing ferroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5407. |
