title: A novel copper(I) complex induces ER-stress-mediated apoptosis and sensitizes B-acute lymphoblastic leukemia cells to chemotherapeutic agents.
abstract: A phosphine copper(I) complex [Cu(thp)4][PF6] (CP) was recently identified as an efficient in vitro antitumor agent. In this study, we evaluated the antiproliferative activity of CP in leukemia cell lines finding a significant efficacy, especially against SEM and RS4;11 cells. Immunoblot analysis showed the activation of caspase-12 and caspase-9 and of the two effector caspase-3 and -7, suggesting that cell death occurred in a caspase-dependent manner. Interestingly we did not observe mitochondrial involvement in the process of cell death. Measures on semipurified proteasome from RS4;11 and SEM cell extracts demonstrated that chymotrypsin-, trypsin- and caspase-like activity decreased in the presence of CP. Moreover, we found an accumulation of ubiquitinated proteins and a remarkable increase of ER stress markers: GRP78, CHOP, and the spliced form of XBP1. Accordingly, the protein synthesis inhibitor cycloheximide significantly protected cancer cells from CP-induced cell death, suggesting that protein synthesis machinery was involved. In well agreement with results obtained on stabilized cell lines, CP induced ER-stress and apoptosis also in primary cells from B-acute lymphoblastic leukemia patients. Importantly, we showed that the combination of CP with some chemotherapeutic drugs displayed a good synergy that strongly affected the survival of both RS4;11 and SEM cells.
authors: Department of Women's and Children's Health, Oncohematology Laboratory, University of Padova, Padova, Italy. These authors contributed equally to this work.
authors: Roberta
authors: R
authors: Bortolozzi
authors: Department of Women's and Children's Health, Oncohematology Laboratory, University of Padova, Padova, Italy. These authors contributed equally to this work.
authors: Giampietro
authors: G
authors: Viola
authors: Department of Women's and Children's Health, Oncohematology Laboratory, University of Padova, Padova, Italy.
authors: Elena
authors: E
authors: Porcù
authors: Department of Women's and Children's Health, Oncohematology Laboratory, University of Padova, Padova, Italy.
authors: Francesca
authors: F
authors: Consolaro
authors: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
authors: Cristina
authors: C
authors: Marzano
authors: School of Science and Technology-Chemistry Division, Università di Camerino, Camerino, Macerata, Italy.
authors: Maura
authors: M
authors: Pellei
authors: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
authors: Valentina
authors: V
authors: Gandin
authors: Department of Women's and Children's Health, Oncohematology Laboratory, University of Padova, Padova, Italy.
authors: Giuseppe
authors: G
authors: Basso
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002414:Cations, Monovalent / Q000494:pharmacology; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000494:pharmacology*; D003300:Copper / Q000494:pharmacology*; D016503:Drug Delivery Systems; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: D002414:Cations, Monovalent; D056831:Coordination Complexes; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D003300:Copper