Investigation of anticancer activity and mechanisms of Meso- 2,3-dimercaptosuccinic acid (DMSA) in glioblastoma cell lines

Abstract

Glioblastoma (GBM) is an aggressive and the most prevalent form of brain tumour. It is characterized by high intertumoral and intratumoral heterogeneity and a low survival rate. Since 2005, the current gold standard of care for treating newly diagnosed GBM has remained the same: maximal safe resection, concomitant chemoradiation (CRT) with temozolomide (TMZ), and adjuvant TMZ. Thus, there is an urgent need to develop more therapeutic interventions for GBM to improve the disease prognosis. Our research group at the University of Wolverhampton has been working on repurposing known FDA approved drugs for cancer treatment. Previous studies from our group have shown that Disulfiram (DS), an FDA approved anti alcoholism drug has excellent anticancer activity against a wide range of cancers with its metal binding capability through its unique dithiol structure. Hence our group is interested in identifying clinically used dithiol compounds which are structurally similar to DS and has metal binding ability to repurpose them as potential anticancer drugs. This study focussed on determining the anticancer activity of Dimercaptosuccinic acid (DMSA), an FDA approved, orally administrated heavy metal chelator, clinically used to treat heavy metal poisoning. DMSA in combination with copper (Cu) exhibits cytotoxicity activity in GBM cell lines. DMSA+Cu, in combination with the conventional GBM drugs such as TMZ, Lomustine (CCNU) and Carmustine (BCNU), showed synergistic cytotoxicity and sensitized the GBM cell lines to first line drugs tested in this study. This study further explored the possible mechanisms of action of DMSA+Cu such as generation of reactive oxygen species (ROS), induction of DNA damage and cell death, inhibition of hypoxia induced stemness and epithelial to mesenchymal transition characteristics, which are the core anticancer mechanisms of DS+Cu. Collectively, our results show that DMSA+Cu induces DNA damage and cytotoxicity in GBM cell lines, in addition to synergistic enhancement of anti-GBM drugs. However, the mechanism of action of DMSA+Cu is very different to that of DS+Cu, especially we observed that DMSA+Cu does not target hypoxia induced cancer stem cell population or generate ROS to induce cytotoxicity. Thus, further studies on the mechanisms of DMSA+Cu induced cytotoxicity will translate DMSA as a potentially novel repurposed therapeutic agent for GBM treatment, due to its easy availability and established safety data.