Disulfiram (DSF) acts as a copper ionophore to induce copper-dependent oxidative stress and mediate anti-tumor efficacy in inflammatory breast cancer.
Disulfiram (DSF) acts as a copper ionophore to induce copper-dependent oxidative stress and mediate anti-tumor efficacy in inflammatory breast cancer.
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DOI：
10.1016/j.molonc.2015.02.007
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发表时间：
2015-06
影响因子：
6.6
通讯作者：
Devi GR
中科院分区：
文献类型：
--
作者：
Allensworth JL;Evans MK;Bertucci F;Aldrich AJ;Festa RA;Finetti P;Ueno NT;Safi R;McDonnell DP;Thiele DJ;Van Laere S;Devi GR
癌细胞通常有活性氧（ROS）水平升高；然而，获得氧化还原适应机制允许逃避ros介导的死亡。炎症性乳腺癌（IBC）是一种独特的晚期BC亚型，其特点是残留疾病和复发率高，尽管多模式治疗取得了进展。使用IBC细胞模型，我们在给予急性剂量的ROS诱导剂后，在存活的IBC细胞中发现了氧化应激反应（OSR）特征。患者样本的Metagene分析显示，与正常或非IBC组织相比，IBC肿瘤样本的OSR评分明显更高，这可能导致IBC肿瘤对常规治疗策略的反应较差，这些治疗策略通常严重依赖ROS诱导。为了对抗这种适应性，我们使用了一种有效的氧化还原调节剂，fda批准的小分子双硫仑（DSF），单独或与铜联合使用。DSF与铜形成络合物（DSF- cu），在体外和体内增加细胞内铜浓度，绕过对膜转运体的需要。在多种IBC细胞模型中，DSF-Cu可拮抗NFκB信号、醛脱氢酶活性和抗氧化水平，诱导氧化应激介导的细胞凋亡。在体内，DSF-Cu能显著抑制肿瘤生长，无明显毒性，仅在肿瘤细胞中引起细胞凋亡。这些结果表明，IBC肿瘤具有高度的氧化还原适应性，这可能使它们对ros诱导疗法产生抗性。通过氧化还原调节，DSF可能是提高晚期BC亚型化疗和/或放射敏感性的有用方法，其中治疗耐药性是对当前标准护理的持久反应的障碍。
Cancer cells often have increased levels of reactive oxygen species (ROS); however, acquisition of redox adaptive mechanisms allows for evasion of ROS-mediated death. Inflammatory breast cancer (IBC) is a distinct, advanced BC subtype characterized by high rates of residual disease and recurrence despite advances in multimodality treatment. Using a cellular model of IBC, we identified an oxidative stress response (OSR) signature in surviving IBC cells after administration of an acute dose of an ROS inducer. Metagene analysis of patient samples revealed significantly higher OSR scores in IBC tumor samples compared to normal or non-IBC tissues, which may contribute to the poor response of IBC tumors to common treatment strategies, which often rely heavily on ROS induction. To combat this adaptation, we utilized a potent redox modulator, the FDA-approved small molecule Disulfiram (DSF), alone and in combination with copper. DSF forms a complex with copper (DSF-Cu) increasing intracellular copper concentration both in vitro and in vivo, bypassing the need for membrane transporters. DSF-Cu antagonized NFκB signaling, aldehyde dehydrogenase activity and antioxidant levels inducing oxidative stress-mediated apoptosis in multiple IBC cellular models. In vivo, DSF-Cu significantly inhibited tumor growth without significant toxicity, causing apoptosis only in tumor cells. These results indicate that IBC tumors are highly redox adapted, which may render them resistant to ROS-inducing therapies. DSF, through redox modulation, may be a useful approach to enhance chemo- and/or radio-sensitivity for advanced BC subtypes where therapeutic resistance is an impediment to durable responses to current standard of care.
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