Integrated Stress Response Activation Induced By Usnic Acid Alleviates BCL-2 Inhibitor ABT-199 Resistance in Acute Myeloid Leukemia

作者：Man Li, Jingjie Dong, Yaonan Hong, Jin Li, Chengtao Sun, Qi Liu, Liqin Li, Xiaoxiao Han, Shengqian Deng, Yue Feng, Yiping Shen, Guoyin Kai, Dijiong Wu · 发表于：Blood · 年份：2024 · DOI：10.1182/blood-2024-198752 · 研究领域：Histone Deacetylase Inhibitors Research、Peptidase Inhibition and Analysis、Ubiquitin and proteasome pathways

Drug resistance is an inevitable issue with targeted therapeutics. A targeted BCL-2 inhibitor, Venetoclax, is approved for newly diagnosed AML cases that can't undergo rigorous chemotherapy when combined with hypomethylating agents. However, most responders eventually develop acquired resistance and experience subsequent tumor progression. Therefore, there is an urgent need for new regimens with reduced toxicity and higher efficacy. Usnic acid, a dibenzofuran compound originating from Usnea diffracta Vain, has potential anticancer effects in various cancers, such as liver, breast, non-small cell lung and colon cancers. Studies utilizing usnic acid against cultured malignant cells have reported its capability of inducing cell cycle arrest, autophagy, and apoptosis. Additionally, usnic acid effectively overcomes the multidrug resistance of K562/Adr cells by enhancing ROS-dependent apoptosis and arresting the cell cycle at G1/G0, indicating its potential as a candidate to synergize with antileukemic drugs. Here, we investigated whether usnic acid at low-cytotoxicity level enhances sensitivity to ABT-199 in cells with acquired ABT-199 resistance and in xenograft model. In this study, MOLM-13 and THP-1 cells were employed to establish ABT-199-resistant AML cell lines, named MOLM-13 R and THP-1 R, with distinct genomic backgrounds (FLT3-ITD mutant in MOLM-13 vs. TP53 mutant in THP-1), which are more likely to develop adaptive resistance to venetoclax-containing combinations. Our re...