Chen Xin, Shi Xianping, Wang Xuejun, Liu Jinbao
State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China.
State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, China ; Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota 57069, USA.
Cancer Cell Microenviron. 2014 Nov 1;1(6). doi: 10.14800/ccm.415.
Patients with chronic myeloid leukemia (CML) are commonly treated with a specific inhibitor of BCR-ABL tyrosine kinase, imatinib mesylate (IM). Unfortunately, CML patients develop IM-resistance, which has emerged as a significant clinical problem. Somatic mutations, especially T315I mutation, in BCR-ABL kinase domain represent the most common mechanism underlying drug resistance to tyrosine kinase inhibitors (TKI), including imatinib. Thus, it is urgent to develop novel therapeutic strategies to overcome TKI-resistance. The anti-rheumatic gold (I) compound Auranofin (AF), was recently approved by US Food and Drug Administration for Phase II clinical trials to treat leukemia. In a recent study, we discovered that AF can selectively inhibit 19S proteasome-associated deubiquitinases (UCHL5 and USP14), which mediates its anticancer effects. More recently studies we have shown that AF inhibits the growth of both Bcr-Abl wild-type cells and IM-resistant Bcr-Abl-T315I mutation cells and . AF-induced Bcr-Abl down regulation is associated with diminished mRNA expression and caspase-dependent Bcr-Abl cleavage. More importantly, we unraveled that AF cytotoxicity is mediated by proteasome inhibition rather than previously suspected reactive oxygen species (ROS) generation. These findings support that AF overcomes IM-resistance through Bcr/Abl-dependent and -independent mechanisms, identifying a potentially new strategy for cancer treatment.
慢性髓性白血病（CML）患者通常接受BCR-ABL酪氨酸激酶的特异性抑制剂甲磺酸伊马替尼（IM）治疗。不幸的是，CML患者会产生IM耐药性，这已成为一个重大的临床问题。BCR-ABL激酶结构域中的体细胞突变，尤其是T315I突变，是对包括伊马替尼在内的酪氨酸激酶抑制剂（TKI）耐药的最常见机制。因此，迫切需要开发新的治疗策略来克服TKI耐药性。抗风湿金（I）化合物金诺芬（AF）最近被美国食品药品监督管理局批准进入治疗白血病的II期临床试验。在最近的一项研究中，我们发现AF可以选择性抑制19S蛋白酶体相关的去泛素化酶（UCHL5和USP14），这介导了其抗癌作用。最近的研究表明，AF抑制Bcr-Abl野生型细胞和IM耐药的Bcr-Abl-T315I突变细胞的生长。AF诱导的Bcr-Abl下调与mRNA表达减少和半胱天冬酶依赖性Bcr-Abl裂解有关。更重要的是，我们发现AF细胞毒性是由蛋白酶体抑制介导的，而不是先前怀疑的活性氧（ROS）生成。这些发现支持AF通过依赖和不依赖Bcr/Abl的机制克服IM耐药性，确定了一种潜在的癌症治疗新策略。
