Novel Thioredoxin reductase 1 inhibitor BS1801 relieves treatment resistance and triggers endoplasmic reticulum stress by elevating reactive oxygen species in glioma

Abstract

Glioma patients will inevitably develop resistance to temozolomide (TMZ) leading to tumor recurrence. By comparing genomic differences between primary and recurrent glioma patients, Thioredoxin reductase 1 (TrxR1) was identified as a crucial role in TMZ resistance. Glioma cells elevate the expression level of TXNRD1 to against TMZ-induced reactive oxygen species (ROS), thereby conferring TMZ resistance. BS1801 is a novel small-molecular targeted drug that binds to Cys497/Sec498 activity site of TrxR1, competitively inhibiting its activity. The results showed that glioblastoma cells were time- and dose-dependently inhibited by BS1801 treatment. Additionally, BS1801 treatment elevated ROS levels, resulting in glioblastoma cell cycle arrest, endoplasmic reticulum (ER) stress, mitochondrial dysfunction and apoptosis. Meanwhile, BS1801 synergized with TMZ to significantly inhibit glioblastoma cell proliferation, induce DNA damage and trigger mitochondrial depolarization. The modified BS1801-nano combined with TMZ treatment significantly prolonged the overall survival of intracranial orthotopic glioma mice models. Finally, a predictive model for BS1801 treatment sensitivity was established using patient-derived GBM organoids. In summary, BS1801 treatment can elevate ROS levels, induce glioblastoma cell apoptosis and activate ER stress, thereby relieving TMZ resistance. BS1801 exhibits potent glioma inhibitory effects and potential clinical application.

Keywords: Endoplasmic reticulum stress; Glioma; Reactive oxygen species; Temozolomide resistance; Thioredoxin reductase inhibitor.