威尼斯人
癌症研究
细胞凋亡
体外
蛋白酶
医学
激活剂(遗传学)
慢性淋巴细胞白血病
免疫学
药理学
生物
化学
内科学
白血病
受体
酶
生物化学
作者
Narjis Fatima,Yandong Shen,Kyle Crassini,Edwin J. Iwanowicz,Henk Lang,Donald S. Karanewsky,Richard I. Christopherson,Stephen P. Mulligan,Giles Best
标识
DOI:10.1101/2022.03.07.483345
摘要
Abstract Despite advances in treatment, a significant proportion of patients with chronic lymphocytic leukaemia (CLL) will relapse with drug-resistant disease. Recent studies demonstrate that the imipridones ONC-201 and ONC-212 and the more potent TR-compounds are effective against a range of different cancers, including acute myeloid leukaemia and tumours of the brain, breast, and prostate. These drugs induce cell death through inhibition of mitochondrial function and activation of the mitochondrial protease, caseinolytic protease (CIpP), and the unfolded protein response (UPR). Here we demonstrate that a drug in this class, TR-57, has efficacy as a single agent and is synergistic with venetoclax against CLL cells cultured under in vitro conditions that mimic the tumour microenvironment. The inhibitory effects of TR-57 on cell survival, proliferation and migration were irrespective of poor-risk features, including aberrations of TP53. Changes in protein expression suggest the mechanisms of action of TR-57 and its synergy with venetoclax involve activation of the UPR, inhibition of the AKT and ERK1/2 pathways and a pro-apoptotic shift in expression of proteins of the BCL-2 family. The study suggests TR-57, as a single agent and in combination with venetoclax, may represent an effective treatment option for CLL, including for patients with poor-risk disease.
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