Brewer George J, Dick Robert, Ullenbruch Matthew R, Jin Hong, Phan Sem H
Department of Human Genetics, University of Michigan, 5022 Kresge Building II, Ann Arbor, MI 48109-0534, USA.
J Inorg Biochem. 2004 Dec;98(12):2160-7. doi: 10.1016/j.jinorgbio.2004.10.006.
Tetrathiomolybdate is an anticopper drug with a unique mechanism of action. Tetrathiomolybdate complexes copper to protein and itself, rendering the copper unavailable for cellular uptake. It was originally developed for Wilson's disease, and is now being developed as an antiangiogenic agent for the treatment of cancer. Many angiogenic cytokines require normal levels of copper, and lowered copper levels reduce cytokine signaling while cellular copper requirements are met. Cytokines of fibrosis and inflammation may be similarly copper dependent, since tetrathiomolybdate inhibits bleomycin induced pulmonary inflammation and fibrosis. The basis for this inhibition was evaluated here by examination of tetrathiomolybdate effects on cytokines in lung pathophysiologically important in the bleomycin mouse model of pulmonary damage. Results in mice injected endotracheally with bleomycin confirmed that tetrathiomolybdate therapy was effective in reducing fibrosis. This effect was associated with significant inhibition of bleomycin-induced tumor necrosis factor alpha and transforming growth factor beta expression in lung homogenates. These effects were shown to be independent of one another. This indicates that tetrathiomolybdate therapy can be effective even when fibrosis is at a more chronic stage, wherein inflammatory cytokines are playing a diminishing role. The inhibition of tumor necrosis factor alpha suggests that diseases of tumor necrosis factor alpha overexpression are also potential targets of tetrathiomolybdate therapy.
四硫代钼酸盐是一种具有独特作用机制的抗铜药物。四硫代钼酸盐将铜与蛋白质及自身结合，使铜无法被细胞摄取。它最初是为治疗威尔逊病而研发的，目前正作为一种抗血管生成剂用于癌症治疗。许多血管生成细胞因子需要正常水平的铜，降低铜水平可减少细胞因子信号传导，同时满足细胞对铜的需求。纤维化和炎症的细胞因子可能同样依赖铜，因为四硫代钼酸盐可抑制博来霉素诱导的肺部炎症和纤维化。在此，通过检测四硫代钼酸盐对博来霉素诱导的肺损伤小鼠模型中对肺部病理生理重要的细胞因子的影响，评估了这种抑制作用的基础。经气管内注射博来霉素的小鼠实验结果证实，四硫代钼酸盐治疗在减轻纤维化方面是有效的。这种效果与肺匀浆中博来霉素诱导的肿瘤坏死因子α和转化生长因子β表达的显著抑制有关。这些作用被证明是相互独立的。这表明即使在纤维化处于更慢性阶段、炎症细胞因子作用减弱时，四硫代钼酸盐治疗也可能有效。肿瘤坏死因子α的抑制表明，肿瘤坏死因子α过表达的疾病也是四硫代钼酸盐治疗的潜在靶点。
