Abramson Family Cancer Research Institute and.
Carcinogenesis. 2014 May;35(5):1067-77. doi: 10.1093/carcin/bgu004. Epub 2014 Jan 9.
Hypoxia-inducible factors (HIFs) accumulate in both neoplastic and inflammatory cells within the tumor microenvironment and impact the progression of a variety of diseases, including colorectal cancer. Pharmacological HIF inhibition represents a novel therapeutic strategy for cancer treatment. We show here that acriflavine (ACF), a naturally occurring compound known to repress HIF transcriptional activity, halts the progression of an autochthonous model of established colitis-associated colon cancer (CAC) in immunocompetent mice. ACF treatment resulted in decreased tumor number, size and advancement (based on histopathological scoring) of CAC. Moreover, ACF treatment corresponded with decreased macrophage infiltration and vascularity in colorectal tumors. Importantly, ACF treatment inhibited the hypoxic induction of M-CSFR, as well as the expression of the angiogenic factor (vascular endothelial growth factor), a canonical HIF target, with little to no impact on the Nuclear factor-kappa B pathway in bone marrow-derived macrophages. These effects probably explain the observed in vivo phenotypes. Finally, an allograft tumor model further confirmed that ACF treatment inhibits tumor growth through HIF-dependent mechanisms. These results suggest pharmacological HIF inhibition in multiple cell types, including epithelial and innate immune cells, significantly limits tumor growth and progression.
缺氧诱导因子（HIFs）在肿瘤微环境中的肿瘤细胞和炎症细胞中积累，并影响多种疾病的进展，包括结直肠癌。抑制 HIF 代表了癌症治疗的一种新的治疗策略。我们在这里表明，吖啶黄素（ACF），一种已知抑制 HIF 转录活性的天然存在的化合物，可阻止免疫功能正常的小鼠中建立的结肠炎相关结肠癌（CAC）的自发模型的进展。ACF 治疗导致 CAC 肿瘤数量、大小和进展（基于组织病理学评分）减少。此外，ACF 治疗与结直肠肿瘤中巨噬细胞浸润和血管生成减少有关。重要的是，ACF 治疗抑制了 M-CSFR 的低氧诱导，以及血管生成因子（血管内皮生长因子）的表达，这是 HIF 的一个典型靶点，对骨髓来源的巨噬细胞中的核因子-κB 途径几乎没有影响。这些作用可能解释了观察到的体内表型。最后，同种异体移植肿瘤模型进一步证实，ACF 治疗通过 HIF 依赖性机制抑制肿瘤生长。这些结果表明，抑制多种细胞类型（包括上皮细胞和固有免疫细胞）中的 HIF 可显著限制肿瘤的生长和进展。
