Disulfiram, an old drug with new potential therapeutic uses for human hematological malignancies.
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.
Department of Experimental Oncology, Mediterranean Institute of Oncology, Via Penninazzo 7, Viagrande, Italy.
Concetta
C
Conticello
Daniela
D
Martinetti
Luana
L
Adamo
Simona
S
Buccheri
Raffaella
R
Giuffrida
Nunziatina
N
Parrinello
Laura
L
Lombardo
Gabriele
G
Anastasi
Gabriella
G
Amato
Maide
M
Cavalli
Annalisa
A
Chiarenza
Ruggero
R
De Maria
Rosario
R
Giustolisi
Massimo
M
Gulisano
Francesco
F
Di Raimondo
D000111:Acetylcysteine / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000096:biosynthesis; D045744:Cell Line, Tumor; D003300:Copper / Q000494:pharmacology*; D004221:Disulfiram / Q000494:pharmacology* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008564:Membrane Potentials / Q000187:drug effects; D051336:Mitochondrial Membranes / Q000187:drug effects; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D003300:Copper; D020169:Caspases; D004221:Disulfiram; D000111:Acetylcysteine