title: Gemcitabine response in pancreatic adenocarcinoma cells is synergistically enhanced by dithiocarbamate derivatives.
abstract: Pancreatic adenocarcinoma is a common malignancy that remains refractory to all available therapies, including the gold standard drug gemcitabine (GEM). We investigated the effect of the combination of GEM and each of the ionophore compounds pyrrolidine dithiocarbamate (PDTC) and disulfiram [DSF; 1-(diethylthiocarbamoyldisulfanyl)-N,N-diethylmethanethioamide] on p53(-/-) pancreatic adenocarcinoma cell growth. PDTC or DSF synergistically inhibited cell proliferation when used in combination with GEM by inducing apoptotic cell death. This effect was associated with an increased mitochondrial O(2)(•-) production and was further enhanced by zinc ions. Basal levels of mitochondrial O(2)(•-) or manganese superoxide dismutase (MnSOD) strictly correlated with the IC(50) for GEM or the percentage of synergism. Thus, the most relevant values of the antiproliferative synergism were obtained in GEM-resistant pancreatic adenocarcinoma cell lines. Interestingly, the GEM-sensitive T3M4 cells transfected with MnSOD expression vector showed mitochondrial O(2)(•-) and IC(50) for GEM similar to those of resistant cell lines. In vivo experiments performed on nude mice xenotransplanted with the GEM-resistant PaCa44 cell line showed that only the combined treatment with GEM and DSF/Zn completely inhibited the growth of the tumoral masses. These results and the consideration that DSF is already used in clinics strongly support the GEM and DSF/Zn combination as a new approach to overcoming pancreatic cancer resistance to standard chemotherapy.
authors.affiliation: Department of Life and Reproduction Sciences, University of Verona, Verona, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Dalla Pozza
authors.forename: Massimo
authors.initials: M
authors.lastname: Donadelli
authors.forename: Chiara
authors.initials: C
authors.lastname: Costanzo
authors.forename: Tatyana
authors.initials: T
authors.lastname: Zaniboni
authors.forename: Ilaria
authors.initials: I
authors.lastname: Dando
authors.forename: Marta
authors.initials: M
authors.lastname: Franchini
authors.forename: Silvia
authors.initials: S
authors.lastname: Arpicco
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.forename: Marta
authors.initials: M
authors.lastname: Palmieri
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D010190:Pancreatic Neoplasms / Q000473:pathology*; D013859:Thiocarbamates / Q000494:pharmacology*; D000093542:Gemcitabine
chemical_list: D013859:Thiocarbamates; D003841:Deoxycytidine; D000093542:Gemcitabine