Diethyldithiocarbamate (Imuthiol) reverses hypoxia-induced chemoresistance in multiple myeloma by targeting hypoxia induced NF-kB pathway


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Gowtham Rajendran1,Vinodh Kanappan1,Basu Supratik2,Weiguang Wang1
1University of Wolverhampton,2The Royal Wolverhampton NHS Trust ยท Department of Haematology

Abstract

Background

Despite the recent progress in treatments options, multiple myeloma (MM) remains challenging to treat with 10-year survival rate of 33% in the UK. The very high relapse rate and chemoresistance of MM could be attributed to the presence of MM cancer stem cells (MM-CSCs). The hypoxic microenvironment of the bone marrow provides a perfect niche for the maintenance and progression of the MM-CSCs through activation of the NF-kB pathway. Hence, drugs that target the CSCs and hypoxia induced NF-kB pathway could provide better clinical outcomes in the treatment of MM. Disulfiram, an anti-alcoholism drug in combination with copper has been shown to eradicate CSCs, inhibit NF-kB and reverse chemoresistance in various cancers. It has been demonstrated that the active metabolite of Disulfiram is diethyldithiocarbamate (imuthiol) which exerts its anticancer properties by forming a complex with copper in vivo. Imuthiol has been previously used in clinics in immunocompromised patients with an excellent safety record. In this study, we investigate the cytotoxic effects of imuthiol in combination with copper in MM cell lines in vitro.

Method

Culture and maintenance of MM cell lines under hypoxic and normoxic conditions, MTT assay, combination index isobologram.

Results

Using three MM cell lines cultured under normoxic and hypoxic conditions, we have demonstrated that the hypoxic cultures significantly induce resistance of MM cell lines to the clinically used first line anticancer drugs lenalidomide, pomalidomide and dexamethasone. We have also showed that imuthiol, in combination with copper, is highly toxic to MM cells in low nanomolar levels (300-600nm). The Imuthiol-Cu complex also synergistically enhanced the cytotoxicity of lenalidomide, pomalidomide and dexamethasone in vitro.

Conclusion

Repurposing existing drugs like Imuthiol for the treatment of MM could greatly reduce the cost and time involved in drug development and provide effective treatment options for MM patients.