Disulfiram, an old drug with new potential therapeutic uses for human hematological malignancies

Abstract

Disulfiram (DSF) is an aldehyde dehydrogenase inhibitor currently used for the treatment of alcoholism. Here, we show that multiple myeloma (MM) cell lines and primary cells from newly diagnosed and relapsed/resistant patients affected by MM, acute myeloid and lymphoblastic leukemia are significantly sensitive to DSF alone and in combination with copper. These effects are present at doses lower than those achievable in vivo after DSF standard administration. The cytotoxic effect achieved by this treatment is comparable to that obtained by conventional chemotherapy and is absent in normal hematopoietic cells. In addition, we found that DSF plus copper induces loss of mitochondrial membrane potential, triggers reactive oxygen species (ROS) production and activates executioner caspases. DSF-copper-induced apoptosis and caspases activation are strongly reversed by antioxidant N-acetylcysteine, thus indicating a critical role of ROS. These results might suggest the use of the old drug DSF, alone or in combination with copper, in the treatment of hematological malignancies.The commonly used alcohol-abuse deterrent disulfiram (DSF) is a member of the dithiocarbamate family, a broad class of molecules with the ability to complex metals, such as copper, and react with sulfhydryl groups and glutathione (GSH). DSF has been used for decades in the treatment of alcoholism for its ability to inhibit irreversibly the aldehyde dehydrogenase.1,2 Several studies from 1970s (e.g., Lewison 1977) 3 have shown that DSF and its metabolites can enhance the effect of some chemotherapeutics, and it is considered a convincing anticancer drug both in vivo and in human patients. The case report described by Lewison was the first on DSF activity against breast cancer.3 Then the compound or its main metabolite was successfully used in a phase II clinical trial with 64 high-risk breast cancer patients and in hepatic metastases and in a patient with stage IV metastatic ocular melanoma. 4 More recently, there are ongoing clinical trials for DSF (Antabuse) as an adjuvant therapy (ClinicalTrials.gov Identifier NCT00312819) or combined with copper gluconate (ClinicalTrials.gov Identifier NCT00742911) against advanced solid cancers. However, a clear explanation for the antitumor effect of DSF is still missing. 2,4It has been shown that association of DSF with copper forms a complex with potent proteasome inhibiting and apoptosis-inducing activity on several tumors, both in vitro and in vivo. 1,2,4-6Moreover, DSF has also been found to reverse the resistance of human tumors to chemotherapeutic drugs by blocking maturation of the P-glycoprotein membrane pump; inhibit activation of nuclear factor-kB; decrease angiogenesis, tumor growth in vivo, matrix metalloproteinases activity and cancer cell invasiveness. 4,5 The proapoptotic activity of DSF has been attributed to redox-related mitochondrial membrane permeabilization, followed by complexation with zinc/copper and inhibition of Zn-dependent matrix metalloproteinases or Cu/Zn superoxide dismutase. The...

Disulfiram when Combined with Copper Enhances the Therapeutic Effects of Temozolomide for the Treatment of Glioblastoma

“…Recently, several independent groups, including this study, have identified DSF through high-throughput screens as a potential therapeutic for the treatment of various cancers including glioblastoma (14)(15)(16)(17)(18)(19). As DSF has been used clinically for over 60 years to treat alcoholism, its pharmacokinetics has been extensively studied and shown to have an excellent safety record at FDArecommended doses (20,21).…”

Stable loading and delivery of disulfiram with mPEG-PLGA/PCL mixed nanoparticles for tumor therapy

“…15,16 Oral DSF as a cancer therapeutic has been tested in several completed and on-going trials (ClinicalTrials.gov Identifier NCT00256230, NCT00742911, NCT01118741), but no positive outcomes have been reported. The poor results following oral administration of DSF are due to its extreme instability A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 5 under physiological conditions; DSF is quickly degraded in the gastrointestinal system, during the hepatic first-pass effect and in the blood stream. 17,18 As a result, orally administered DSF does not reach tumor tissues at therapeutic concentrations, which is a major limitation for the clinical usage of DSF in cancer treatment.…”

“…4 In recent years, researchers have discovered that DSF and its metabolites may have antitumor and chemosensitizing activities, possibly through inhibition of proteasome activity. [5][6][7][8] In fact, high-throughput screening has identified DSF as a potential therapeutic for triple-negative breast cancer cells, breast cancer stem cells and human glioblastoma stem cells by modulating ROS-MAPK and NFκB pathways. 9-12 DSF also permanently inactivates the human multidrug resistance p-glycoprotein and has been approved for prevention of related cases of drug resistance.…”

Delivery of disulfiram into breast cancer cells using folate-receptor-targeted PLGA-PEG nanoparticles: in vitro and in vivo investigations

“…Disulfiram (DS), a member of dithiocarbamate family with 297 Da molecular weight, is oral aldehyde dehydrogenase (ALDH) inhibitor that has been used in the treatment of alcoholism since 1940s [1–3]. During the last few years, a growing body of evidence from both in vivo and in vitro studies indicated that disulfiram has anticancer properties [2].…”