Integrated stress response activation induced by usnic acid alleviates BCL-2 inhibitor ABT-199 resistance in acute myeloid leukemia

作者：Dijiong Wu, Man Li, Yaonan Hong, Jin Li, Qi Liu, Chengtao Sun, Liqin Li, Xiaoxiao Han, Shengqian Deng, Feng Yue, Yiping Shen, Guoyin Kai · 发表于：Journal of Advanced Research · 年份：2024 · DOI：10.1016/j.jare.2024.10.003 · 被引用次数：11 · 研究领域：Lichen and fungal ecology、Microbial Natural Products and Biosynthesis、Biological Activity of Diterpenoids and Biflavonoids

The cotreatment of ABT-199 and usnic acid induced ISR activation through HRI with increased expression levels of the transcription factors ATF4, CHOP, and the pro-apoptotic protein NOXA, and the downregulation of anti-apoptotic protein MCL-1 through proteasomal degradation. The increase in the NOXA levels coupled with the reduction in MCL-1 levels caused by combined therapy, is most likely correlated with the recovery of sensitivity recovery in ABT-199-resistant cells. • Acquired resistance to BCL-2 inhibitor (ABT-199) in AML remains a critical clinical challenge. • Usnic acid at low toxicity dose synergistically anti-AML with ABT-199 both in in vitro and in vivo. • MCL-1 protein strongly degraded with the co-treatment of usnic acid and ABT-199. • The deduced MCL-1 may triggered by the activation of integrated stress response induced by usnic acid. • HRI kinase activation plays a critical role in the process of ISR induced MCL-1 degradation. ABT-199 (venetoclax) is a BCL-2 suppressor with pronounced effects on acute myeloid leukemia (AML). However, its usefulness as a monotherapy or in combination with hypomethylating medicines like azacitidine is debatable due to acquired resistance. Usnic acid, a dibenzofuran extracted from lichen Usnea diffracta Vain, exhibits anticancer properties and may counteract multidrug resistance in leukemia cells. This study investigated whether usnic acid at low-cytotoxicity level could enhance sensitivity of AML cells with acquired resistance to...