Cross-talk between two antioxidants, thioredoxin reductase and heme oxygenase-1, and therapeutic implications for multiple myeloma.
Cross-talk between two antioxidants, thioredoxin reductase and heme oxygenase-1, and therapeutic implications for multiple myeloma.
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DOI：
10.1016/j.redox.2016.01.007
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发表时间：
2016-08
期刊：
影响因子：
11.4
通讯作者：
Tonissen KF
中科院分区：
文献类型：
--
作者：
Raninga PV;Di Trapani G;Vuckovic S;Tonissen KF
多发性骨髓瘤(MM)的特征是异常克隆性浆细胞在骨髓中聚集。尽管最近在抗骨髓瘤治疗方面取得了进展，多发性骨髓瘤仍然是一种不治之症。抗氧化剂分子在许多癌症中上调，与肿瘤的增殖、生存和化疗耐药相关，因此，已被认为是潜在的治疗靶点。本研究探讨了两种抗氧化剂硫氧还蛋白还原酶(TrxR)和血红素加氧酶-1(HO-1)之间的相互作用及其在MM中的治疗意义。结果发现，尽管TrxR抑制剂Auranofin在较低浓度时显著抑制TrxR活性超过50%，但只有在较高浓度的Auranofin时才能抑制骨髓瘤细胞的增殖。用较低浓度的金诺芬抑制TrxR诱导骨髓瘤细胞HO-1蛋白表达。使用亚致死浓度的Auranofin抑制TrxR活性，同时抑制HO-1，可显著抑制骨髓瘤细胞的生长并诱导细胞凋亡。TrxR通过Nrf2信号通路以一种ROS依赖的方式调节HO-1。与亲本细胞相比，耐药骨髓瘤细胞中HO-1mRNA水平升高，抑制HO-1可恢复耐药骨髓瘤细胞对波特佐米的敏感性。这些发现表明，同时抑制HO-1与TrxR抑制剂或与Bortezomib一起使用将改善MM患者的治疗结果。因此，我们的发现进一步支持了单独或与其他治疗药物联合靶向多种抗氧化系统以改善多发性骨髓瘤患者的治疗结果的必要性。TrxR抑制可诱导骨髓瘤细胞HO-1的表达。抑制TrxR和HO-1共同诱导骨髓瘤细胞凋亡。在TrxR抑制的骨髓瘤细胞中，HO-1是一种次级抗凋亡机制。抑制HO-1可克服骨髓瘤细胞对波特佐米的耐药性。
Multiple myeloma (MM) is characterized by an accumulation of abnormal clonal plasma cells in the bone marrow. Despite recent advancements in anti-myeloma therapies, MM remains an incurable disease. Antioxidant molecules are upregulated in many cancers, correlating with tumor proliferation, survival, and chemoresistance and therefore, have been suggested as potential therapeutic targets. This study investigated the cross-talk between two antioxidant molecules, thioredoxin reductase (TrxR) and heme oxygenase-1 (HO-1), and their therapeutic implications in MM. We found that although auranofin, a TrxR inhibitor, significantly inhibited TrxR activity by more than 50% at lower concentrations, myeloma cell proliferation was only inhibited at higher concentrations of auranofin. Inhibition of TrxR using lower auranofin concentrations induced HO-1 protein expression in myeloma cells. Using a sub-lethal concentration of auranofin to inhibit TrxR activity in conjunction with HO-1 inhibition significantly decreased myeloma cell growth and induced apoptosis. TrxR was shown to regulate HO-1 via the Nrf2 signaling pathway in a ROS-dependent manner. Increased HO-1 mRNA levels were observed in bortezomib-resistant myeloma cells compared to parent cells and HO-1 inhibition restored the sensitivity to bortezomib in bortezomib-resistant myeloma cells. These findings indicate that concurrent inhibition of HO-1 with either a TrxR inhibitor or with bortezomib would improve therapeutic outcomes in MM patients. Hence, our findings further support the need to target multiple antioxidant systems alone or in combination with other therapeutics to improve therapeutic outcomes in MM patients. TrxR inhibition induces HO-1 expression in myeloma cells. Inhibiting TrxR and HO-1 together induces myeloma cell apoptosis. HO-1 serves as a secondary anti-apoptotic mechanism in TrxR-inhibited myeloma cells. HO-1 inhibition overcomes bortezomib resistance in myeloma cells.