Department of Pharmacology and Toxicology, Massey Cancer Center, Virginia Commonwealth University, 401 College St., Richmond, VA 23298, USA.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt.
Int J Mol Sci. 2023 Aug 11;24(16):12669. doi: 10.3390/ijms241612669.
The bromodomain and extra-terminal domain (BET) family inhibitors are small molecules that target the dysregulated epigenetic readers, BRD2, BRD3, BRD4 and BRDT, at various transcription-related sites, including super-enhancers. BET inhibitors are currently under investigation both in pre-clinical cell culture and tumor-bearing animal models, as well as in clinical trials. However, as is the case with other chemotherapeutic modalities, the development of resistance is likely to constrain the therapeutic benefits of this strategy. One tumor cell survival mechanism that has been studied for decades is autophagy. Although four different functions of autophagy have been identified in the literature (cytoprotective, cytotoxic, cytostatic and non-protective), primarily the cytoprotective and cytotoxic forms appear to function in different experimental models exposed to BET inhibitors (with some evidence for the cytostatic form). This review provides an overview of the cytoprotective, cytotoxic and cytostatic functions of autophagy in response to BET inhibitors in various tumor models. Our aim is to determine whether autophagy targeting or modulation could represent an effective therapeutic strategy to enhance the response to these modalities and also potentially overcome resistance to BET inhibition.
溴结构域和末端结构域（BET）家族抑制剂是靶向失调的表观遗传读蛋白 BRD2、BRD3、BRD4 和 BRDT 的小分子，这些读蛋白在包括超级增强子在内的各种转录相关位点发挥作用。BET 抑制剂目前正在临床前细胞培养和荷瘤动物模型以及临床试验中进行研究。然而，与其他化疗方式一样，耐药性的发展可能会限制这种策略的治疗益处。几十年来，细胞自噬一直是一种被研究的肿瘤细胞存活机制。尽管文献中已经确定了自噬的四种不同功能（细胞保护、细胞毒性、细胞静止和非保护），但主要是细胞保护和细胞毒性形式似乎在不同的实验模型中对 BET 抑制剂起作用（有一些证据表明细胞静止形式也起作用）。这篇综述概述了自噬在各种肿瘤模型中对 BET 抑制剂的细胞保护、细胞毒性和细胞静止功能。我们的目的是确定自噬靶向或调节是否可以代表一种有效的治疗策略，以增强对这些方式的反应，并有可能克服对 BET 抑制的耐药性。
