HIF-1 Signaling in Drug Resistance to Chemotherapy
HIF-1 Signaling in Drug Resistance to Chemotherapy
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DOI：
10.2174/0929867321666140414101056
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发表时间：
2014-01-01
影响因子：
4.1
通讯作者：
El-Deiry, W. S.
中科院分区：
文献类型：
--
作者：
Warfel, N. A.;El-Deiry, W. S.
由于肿瘤缺氧和表观遗传机制，在广泛的人类癌症中观察到缺氧诱导因子1 （HIF-1）信号的激活。HIF-1的激活可导致大量靶基因的转录，这些基因可促进与治疗耐药性相关的生理变化，包括抑制细胞凋亡和衰老以及激活药物外排和细胞代谢。因此，靶向HIF-1代表了一种有吸引力的策略，可以提高当前治疗的疗效，并降低肿瘤对化疗的耐药性。抑制HIF-1信号传导的方法主要集中在通过诱导其降解或抑制其转录、抑制HIF-1介导的转录或破坏HIF-1转录因子复合物的形成来降低HIF-1 α蛋白水平。迄今为止，已经确定了多种临床前和临床药物通过各种机制有效抑制HIF-1活性，这可能是其抗肿瘤功效的一部分。本综述旨在概述我们目前对HIF-1在治疗耐药中的作用的理解，并讨论正在进行的开发HIF-1抑制剂作为抗癌策略的努力。
Activation of hypoxia-inducible factor 1 (HIF-1) signaling is observed in a broad range of human cancers due to tumor hypoxia and epigenetic mechanisms. HIF-1 activation leads to the transcription of a plethora of target genes that promote physiological changes associated with therapeutic resistance, including the inhibition of apoptosis and senescence and the activation of drug efflux and cellular metabolism. As a result, targeting HIF-1 represents an attractive strategy to enhance the efficacy of current therapies as well as reduce resistance to chemotherapy in tumors. Approaches to inhibit HIF-1 signaling have primarily focused on reducing HIF-1 alpha protein levels, by inducing its degradation or inhibiting its transcription, inhibiting HIF-1-mediated transcription, or disrupting the formation of the HIF-1 transcription factor complex. To date, multiple preclinical and clinical agents have been identified that effectively inhibit HIF-1 activity through various mechanisms, likely accounting for a portion of their anti-tumor efficacy. This review aims to provide an overview of our current understanding of the role of HIF-1 in therapeutic resistance and discuss the ongoing effort to develop HIF-1 inhibitors as an anti-cancer strategy.