Thoracic Oncology Research Laboratory, University of Pennsylvania School of Medicine, 1016B ARC, 3615 Civic Center Boulevard, Philadelphia, PA 19104-4318, USA.
Biochem Pharmacol. 2011 Nov 1;82(9):1175-85. doi: 10.1016/j.bcp.2011.07.086. Epub 2011 Jul 26.
The small molecule anti-tumor agent, 5,6-dimethylxanthenone-4-acetic acid (DMXAA, now called Vadimezan) is a potent macrophage and dendritic cell activating agent that, in the murine system, results in the release of large amounts of cytokines and chemokines. The mechanisms by which this release is mediated have not been fully elucidated. The mitogen-activated protein kinase (MAPK) pathways play an important role in the regulation of proinflammatory cytokines, such as TNF-α, IL-1β, as well as the responses to extracellular stimuli, such as lipopolysaccharide (LPS). The results of this study demonstrate that DMXAA activates three members of mitogen-activated protein kinase (MAPK) superfamily, namely p38 MAPK, extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2), and c-Jun N-terminal kinases (JNKs) via a RIP2-independent mechanism in murine macrophages. By using selective inhibitors of MAPKs, this study confirms that both activated p38/MK2 pathways and ERK1/2 MAPK play a significant role in regulation of both TNF-α and IL-6 protein production induced by DMXAA at the post-transcriptional level. Our findings also show that interferon-γ priming can dramatically augment TNF-α protein secretion induced by DMXAA through enhancing activation of multiple MAPK pathways at the post-transcriptional level. This study expands current knowledge on mechanisms of how DMXAA acts as a potent anti-tumor agent in murine system and also provides useful information for further study on the mechanism of action of this potential anti-tumor compound in human macrophages.
小分子抗肿瘤剂 5,6-二甲基黄嘌呤-4-乙酸（DMXAA，现称 Vadimezan）是一种有效的巨噬细胞和树突状细胞激活剂，在小鼠系统中，会导致大量细胞因子和趋化因子的释放。介导这种释放的机制尚未完全阐明。丝裂原激活的蛋白激酶（MAPK）途径在调节促炎细胞因子（如 TNF-α、IL-1β）以及对细胞外刺激（如脂多糖（LPS））的反应中起着重要作用。这项研究的结果表明，DMXAA 通过一种不依赖于 RIP2 的机制激活丝裂原激活的蛋白激酶（MAPK）超家族的三个成员，即 p38 MAPK、细胞外信号调节激酶 1 和 2（ERK1 和 ERK2）以及 c-Jun N-末端激酶（JNKs）。通过使用 MAPK 的选择性抑制剂，本研究证实，激活的 p38/MK2 途径和 ERK1/2 MAPK 在调节 DMXAA 诱导的 TNF-α 和 IL-6 蛋白产生的转录后水平均发挥重要作用。我们的研究结果还表明，干扰素-γ 引发可以通过增强转录后水平多种 MAPK 途径的激活，显著增加 DMXAA 诱导的 TNF-α 蛋白分泌。这项研究扩展了目前关于 DMXAA 作为一种有效的抗肿瘤剂在小鼠系统中作用机制的知识，也为进一步研究这种潜在的抗肿瘤化合物在人类巨噬细胞中的作用机制提供了有用的信息。
