Raninga Prahlad V, Di Trapani Giovanna, Vuckovic Slavica, Bhatia Maneet, Tonissen Kathryn F
School of Natural Sciences, Griffith University, Nathan, QLD, Australia.
Eskitis Institute for Drug Discovery, Griffith University, Nathan, QLD, Australia.
Oncotarget. 2015 Jun 20;6(17):15410-24. doi: 10.18632/oncotarget.3795.
Multiple myeloma (MM) is a hematological malignancy characterized by the aberrant accumulation of clonal plasma cells in the bone marrow. Despite recent advancement in anti-myeloma treatment, MM remains an incurable disease. This study showed higher intrinsic oxidative stress and higher Trx1 and TrxR1 protein levels in MM cells compared to normal cells. Drug-induced Trx1 (PX-12) and TrxR1 (Auranofin) inhibition disrupted redox homeostasis resulting in ROS-induced apoptosis in MM cells and a reduction in clonogenic activity. Knockdown of either Trx1 or TrxR1 reduced MM cell viability. Trx1 inhibition by PX-12 sensitized MM cells to undergo apoptosis in response to the NF-κβ inhibitors, BAY 11-7082 and curcumin. PX-12 treatment decreased the expression of the NF-κβ subunit p65 in MM cells. Bortezomib-resistant MM cells contained higher Trx1 protein levels compared to the parental cells and PX-12 treatment resulted in apoptosis. Thus, increased Trx1 enhances MM cell growth and survival and exerts resistance to NF-κβ inhibitors. Therefore inhibiting the thioredoxin system may be an effective therapeutic strategy to treat newly diagnosed as well as relapsed/refractory MM.
多发性骨髓瘤（MM）是一种血液系统恶性肿瘤，其特征是骨髓中克隆性浆细胞异常积聚。尽管抗骨髓瘤治疗最近取得了进展，但MM仍然是一种无法治愈的疾病。这项研究表明，与正常细胞相比，MM细胞具有更高的内在氧化应激以及更高的硫氧还蛋白1（Trx1）和硫氧还蛋白还原酶1（TrxR1）蛋白水平。药物诱导的Trx1（PX - 12）和TrxR1（金诺芬）抑制作用破坏了氧化还原稳态，导致MM细胞中活性氧（ROS）诱导的细胞凋亡以及克隆形成活性降低。敲低Trx1或TrxR1均可降低MM细胞活力。PX - 12对Trx1的抑制作用使MM细胞对NF - κβ抑制剂BAY 11 - 7082和姜黄素诱导的细胞凋亡敏感。PX - 12处理降低了MM细胞中NF - κβ亚基p65的表达。与亲本细胞相比，硼替佐米耐药的MM细胞含有更高水平的Trx1蛋白，PX - 12处理可导致细胞凋亡。因此，Trx1水平升高促进了MM细胞的生长和存活，并使其对NF - κβ抑制剂产生耐药性。所以，抑制硫氧还蛋白系统可能是治疗新诊断以及复发/难治性MM的一种有效治疗策略。
