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.

• Authors: Concetta Conticello, Daniela Martinetti, Luana Adamo, Simona Buccheri, Raffaella Giuffrida, Nunziatina Parrinello, Laura Lombardo, Gabriele Anastasi, Gabriella Amato, Maide Cavalli, Annalisa Chiarenza, Ruggero De Maria, Rosario Giustolisi, Massimo Gulisano, Francesco Di Raimondo
• Journal: International journal of cancer (Int J Cancer) Vol. 131 Issue 9 Pg. 2197-203 (Nov 01 2012) ISSN: 1097-0215 [Electronic] United States
• PMID: 22322883 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 UICC.

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Free Radical Scavengers
• Reactive Oxygen Species
• Copper
• Caspases
• Disulfiram
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Caspases (biosynthesis)
• Cell Line, Tumor
• Copper (pharmacology)
• Disulfiram (pharmacology, therapeutic use)
• Enzyme Inhibitors (pharmacology)
• Free Radical Scavengers (pharmacology)
• Humans
• Leukemia, Myeloid, Acute (drug therapy, metabolism, pathology)
• Membrane Potentials (drug effects)
• Mitochondrial Membranes (drug effects)
• Multiple Myeloma (drug therapy, metabolism, pathology)
• Oxidative Stress (drug effects)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, metabolism, pathology)
• Reactive Oxygen Species (metabolism)