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PLGA-Nano-Encapsulated Disulfiram Inhibits Cancer Stem Cells and Targets Non-Small Cell Lung Cancer In Vitro and In
Kate Butcher1,2, Zhipeng Wang1, Sathishkumar Kurusamy1,3
1Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton WV1 1LY, UK.
Abstract:
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 in vitro 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.
Insights
Hypoxia promotes cancer stem cell traits and drug resistance in non-small cell lung cancer (NSCLC). The drug disulfiram, delivered via nanoparticles, effectively combats these resistant NSCLC cells, offering a promising new therapeutic strategy.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Cancer stem cells (CSCs) are crucial drivers of non-small cell lung cancer (NSCLC) chemoresistance and metastasis.
- Hypoxia is implicated in maintaining CSC traits and drug resistance.
Purpose of the Study:
- To investigate the role of hypoxia in inducing and maintaining CSC traits in NSCLC.
- To evaluate the anti-CSC effects of disulfiram (DS) and its nanoparticle formulation (DS-PLGA).
Main Methods:
- Utilized two NSCLC cell lines to study hypoxia-induced stemness and chemoresistance.
- Investigated the role of the NF-κB pathway.
- Assessed the in vitro and in vivo efficacy of disulfiram and DS-PLGA, including combination therapy with copper gluconate.
Main Results:
- Hypoxia significantly induced stemness and chemoresistance in NSCLC cells.
- Disulfiram demonstrated potent in vitro anti-CSC activity, blocking sphere formation and enhancing chemotherapy drug efficacy.
- DS-PLGA combined with copper gluconate showed significant anticancer efficacy in a metastatic NSCLC mouse model.
Conclusions:
- Hypoxia-induced stemness and chemoresistance in NSCLC are mediated by pathways including NF-κB.
- Disulfiram, particularly in a nanoparticle formulation (DS-PLGA) with copper, presents a promising therapeutic strategy against NSCLC CSCs and metastasis.
