A novel copper(I) complex induces ER-stress-mediated apoptosis and sensitizes B-acute lymphoblastic leukemia cells to chemotherapeutic agents
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Roberta Bortolozzi1,*, Giampietro Viola1,*, Elena Porcù1, Francesca Consolaro1, Cristina Marzano2, Maura Pellei3, Valentina Gandin2, Giuseppe Basso1
1 Department of Women’s and Children’s health, Oncohematology laboratory, University of Padova, Padova, Italy
2 Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
3 School of Science and Technology-Chemistry Division, Università di Camerino, Camerino, Macerata, Italy
* These authors contributed eually to this work
Giampietro Viola, email:
Keywords: Acute lymphoblastic leukemia; ER stress; apoptosis; copper complexes
Received: March 31, 2014 Accepted: May 26, 2014 Published: May 27, 2014
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.
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