Butcher Kate, Wang Zhipeng, Kurusamy Sathishkumar, Zhang Zaixing, Morris Mark R, Najlah Mohammad, McConville Christopher, Kannappan Vinodh, Wang Weiguang
Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton WV1 1LY, UK.
Disulfican Ltd., Wolverhampton WV9 5HD, UK.
Biomolecules. 2024 Dec 23;14(12):1651. doi: 10.3390/biom14121651.
Cancer stem cells (CSCs) play a key role in non-small cell lung cancer (NSCLC) chemoresistance and metastasis. In this study, we used two NSCLC cell lines to investigate the regulating effect of hypoxia in the induction and maintenance of CSC traits. Our study demonstrated hypoxia-induced stemness and chemoresistance at levels comparable to those in typical CSC sphere culture. Activation of the NF-κB pathway (by transfection of NF-κB-p65) plays a key role in NSCLC CSCs and chemoresistance. Disulfiram (DS), an anti-alcoholism drug, showed a strong anti-CSC effect. It blocked cancer cell sphere reformation and clonogenicity, synergistically enhanced the cytotoxicity of four anti-NSCLC drugs (doxorubicin, gemcitabine, oxaliplatin and paclitaxel) and reversed hypoxia-induced resistance. The effect of DS on CSCs is copper-dependent. A very short half-life in the bloodstream is the major limitation for the translation of DS into a cancer treatment. Our team previously developed a poly lactic-co-glycolic acid (PLGA) nanoparticle encapsulated DS (DS-PLGA) with a long half-life in the bloodstream. Intra venous injection of DS-PLGA in combination with the oral application of copper gluconate has strong anticancer efficacy in a metastatic NSCLC mouse model. Further study may be able to translate DS-PLGA into cancer applications.
癌症干细胞（CSCs）在非小细胞肺癌（NSCLC）的化疗耐药性和转移中起关键作用。在本研究中，我们使用两种NSCLC细胞系来研究缺氧在CSC特性诱导和维持中的调节作用。我们的研究表明，缺氧诱导的干性和化疗耐药性水平与典型的CSC球状体培养相当。NF-κB途径的激活（通过转染NF-κB-p65）在NSCLC CSCs和化疗耐药性中起关键作用。双硫仑（DS），一种戒酒药物，显示出强大的抗CSC作用。它阻止癌细胞球体重塑和克隆形成，协同增强四种抗NSCLC药物（阿霉素、吉西他滨、奥沙利铂和紫杉醇）的细胞毒性，并逆转缺氧诱导的耐药性。DS对CSCs的作用是铜依赖性的。在血液中半衰期非常短是将DS转化为癌症治疗的主要限制。我们团队之前开发了一种聚乳酸-乙醇酸共聚物（PLGA）纳米颗粒包裹的DS（DS-PLGA），其在血液中的半衰期很长。在转移性NSCLC小鼠模型中，静脉注射DS-PLGA并联合口服葡萄糖酸铜具有很强的抗癌效果。进一步的研究可能能够将DS-PLGA转化为癌症应用。
