Disulfiram May Contribute To Apoptosis Of Myeloma Cells By Reactivating Of Cell Cycle Regulating Gene Cdkn2a

Objective: Multiple myeloma (MM) is an incurable plasma-cell dyscrasia characterized by uncontrolled growth of malignant plasma cells in the bone marrow. Proteasome inhibitor bortezomib is a frontline MM drug, however acquired resistance to bortezomib remains a clinical hurdle. Disulfiram (tetraethylthiuram disulfide, DSF) belongs to promising cancer-killing drugs, and although the mechanism of its anticancer activity remains unclear, it has been suggested that this drug inhibits proteasome activity. Furthermore, disulfiram contains strong thio-reactive functional groups and since the catalytic mechanism of DNA methyltransferases (DNMTs) involves the covalent attack at the C6 position of cytosine by the thiol group of the catalytic cysteine on the DNMT enzyme, the DSF can function as DNMT non-nucleoside inhibitor with possible gene demethylation´s effect. On the other hand, DNMT inhibitors, 5-azacytidine (AZA) and 5-aza-2´-deoxycytidine (DAC) are nucleoside analogs, whose mechanism of action involves incorporation of the aza-modified base into DNA during DNA synthesis with subsequent covalent trapping of the DNMT enzyme. Therefore, these nucleoside analogs (AZA and DAC) can have significant cytotoxicity and can lead to major adverse effects, including myelosuppression, when administered to patients.