title: Synergistic cytotoxicity of gemcitabine, clofarabine and edelfosine in lymphoma cell lines.
abstract: Treatments for lymphomas include gemcitabine (Gem) and clofarabine (Clo) which inhibit DNA synthesis. To improve their cytotoxicity, we studied their synergism with the alkyl phospholipid edelfosine (Ed). Exposure of the J45.01 and SUP-T1 (T-cell) and the OCI-LY10 (B-cell) lymphoma cell lines to IC10-IC20 levels of the drugs resulted in strong synergistic cytotoxicity for the 3-drug combination based on various assays of cell proliferation and apoptosis. Cell death correlated with increased phosphorylation of histone 2AX and KAP1, decreased mitochondrial transmembrane potential, increased production of reactive oxygen species and release of pro-apoptotic factors. Caspase 8-negative I9.2 cells were considerably more resistant to [Gem+Clo+Ed] than caspase 8-positive cells. In all three cell lines [Gem+Clo+Ed] decreased the level of phosphorylation of the pro-survival protein AKT and activated the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) stress signaling pathway, which in J45.01 cells resulted in the phosphorylation and heterodimerization of the transcription factors ATF2 and c-Jun. The observed rational mechanism-based efficacy of [Gem+Clo+Ed] based on the synergistic convergence of several pro-death and anti-apoptotic signaling pathways in three very different cell backgrounds provides a powerful foundation for undertaking clinical trials of this drug combination for the treatment of lymphomas.
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: B C
authors.initials: BC
authors.lastname: Valdez
authors.affiliation: Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: A R
authors.initials: AR
authors.lastname: Zander
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: G
authors.initials: G
authors.lastname: Song
authors.affiliation: Department of Experimental Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Murray
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Nieto
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: R E
authors.initials: RE
authors.lastname: Champlin
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: B S
authors.initials: BS
authors.lastname: Andersson