Department of Structural and Functional Biology, University of Insubria, Busto Arsizio, Varese, Italy.
Curr Mol Pharmacol. 2011 Jan;4(1):62-77. doi: 10.2174/1874467211104010062.
Cells in rapidly growing solid tumors are commonly exposed to chronic or intermittent hypoxia. Hypoxia can induce cell death by multiple mechanisms; however, some cells may adapt by orchestrating dramatic changes in gene expression patterns. In addition, hypoxia exerts a powerful selective pressure on tumor cells, resulting in the emergence of clonal populations whose defects in DNA repair mechanisms favor genomic instability and tumor progression, whereas disabling of apoptotic pathways makes them more resistant to both environmental stresses and therapeutic interventions. The transcriptional factor HIF-1 (Hypoxia-Inducible Factor 1) is generally considered as the major regulator of the hypoxic adaptive response, and as such it is viewed as a viable prospective target for novel pharmacologic approaches to the clinical management of solid tumors. Several agents have been identified that inhibit HIF1 transcriptional activity, and some of them are currently undergoing clinical trials, mostly based on their antiangiogenic properties. This article reviews the role played by HIF-1 in tumorigenesis and chemoresistance and provides an overview of current and prospective pharmacologic strategies designed to inhibit HIF-1 activity, emphasizing their direct and indirect effects on tumor growth, as well as their potential for chemoprevention and chemosensitization.
快速生长的实体瘤中的细胞通常会受到慢性或间歇性缺氧的影响。缺氧可以通过多种机制诱导细胞死亡；然而，一些细胞可能通过协调基因表达模式的剧烈变化来适应。此外，缺氧对肿瘤细胞施加了强大的选择压力，导致出现克隆群体，其 DNA 修复机制缺陷有利于基因组不稳定性和肿瘤进展，而凋亡途径的失活使它们对环境压力和治疗干预更具抵抗力。转录因子 HIF-1（缺氧诱导因子 1）通常被认为是缺氧适应反应的主要调节剂，因此它被视为治疗实体瘤的新型药物治疗方法的可行潜在靶点。已经确定了几种抑制 HIF1 转录活性的药物，其中一些正在进行临床试验，主要基于它们的抗血管生成特性。本文综述了 HIF-1 在肿瘤发生和化疗耐药中的作用，并概述了目前和未来旨在抑制 HIF-1 活性的药物治疗策略，强调了它们对肿瘤生长的直接和间接影响，以及它们在化学预防和化学增敏方面的潜力。
