Disulfiram suppresses malignant mesothelioma in vitro and in vivo by targeting hypoxia induced NF-kB pathway and cancer stem cells


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Vinodh Kannappan1,Zaixing Zhang2,Hemapriya Mahendran3,Gowtham Rajendran3,Peng Liu4,Yaohe Wang4,Peter Szlosarek4,Zhipeng Wang2,Michael Antonysamy3,Weiguang Wang2
1University of Wolverhampton,2Research Institute in Healthcare Science, Faculty of Science & Engineering, University of Wolverhampton,3PSG College of Arts and Science, Coimbatore, Tamilnadu, India,4Barts Cancer Institute, Queen Mary University of London

Abstract

Background

Malignant mesothelioma (MM) is a rare but very aggressive cancer with increasing incidence worldwide. The current multimodal treatment with cisplatin/pemetrexed is not effective and the overall survival rate remains only 9-12 months. MM contains cancer stem cells (MM-CSCs) that promotes chemoresistance, metastasis and recurrence leading to poor prognosis. Eidence indicate that the hypoxic milieu of MM activates NFkB pathway and induces PD-L1 expression that aids the maintenance of MM-CSCs and allows MM to escape host immune system. Therefore, development of drugs simultaneously targeting hypoxia-NFkB-CSCs axis and PD-L1 would improve the therapeutic outcomes of MM.

We have demonstrated that Disulfiram (DS), a long-established anti-alcoholism drug, in combination with copper (Cu) can effectively inhibit NFkB, eradicate CSCs and reverse chemoresistance in many cancers. DS/Cu also potentiates the cytotoxicity of many first-line chemotherapeutic drugs. Despite being effective in vitro, the clinical application of DS for MM treatment is limited by its short half-life (<2 minutes) in the bloodstream. Recently, we developed a novel injectable cyclodextrin formulation of DS (CD-DS) which has better solubility and longer half-life.

Method

Normoxic and hypoxic cultures of MM cells, MTT cytotoxicity, Westernblot, CSC marker detection, immunocytochemistry, combination index-isobologram, migration, invasion, xenograft MM mouse models.

Results

Hypoxic MM cells are highly resistant to Cisplatin/Pemetrexed and showed increased expression of NFkB and CSC markers such as ALDH, CD133 and ABCG2. CD-DS/Cu completely reversed hypoxia induced chemoresistance and induced apoptosis at low nanomolar levels (IC50s: 100-200nM). CD-DS/Cu inhibited the hypoxia-induced NF-kB and PD-L1 expression and blocked the migration and invasion of MM cells. CD-DS/Cu synergistically enhanced the cytotoxic effect of cisplatin/pemetrexed.  CD-DS/Cu significantly extended the survival rate of MM xenograft models showing curative effect on MM with low/no toxicity to vital organs.

Conclusion

As an FDA approved drug with all preclinical data available, DS is a perfect candidate for MM treatment.