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Mechanistic studies on the synergistic cytotoxicity of the nucleoside analogs gemcitabine and clofarabine in multiple myeloma: relevance of p53 and its clinical implications.
|Title||Mechanistic studies on the synergistic cytotoxicity of the nucleoside analogs gemcitabine and clofarabine in multiple myeloma: relevance of p53 and its clinical implications.|
|Publication Type||Journal Article|
|Year of Publication||2013|
|Authors||Valdez BC, Wang G, Murray D, Nieto Y, Li Y, Shah J, Turturro F, Wang M, Weber DM, Champlin RE, Qazilbash MH, Andersson BS|
|Date Published||2013 Aug|
Hematopoietic stem cell transplantation (HSCT) is an established treatment for multiple myeloma (MM), a plasma cell malignancy. To identify an improved pretransplant conditioning regimen, we investigated the cytotoxicity of gemcitabine (Gem) and clofarabine (Clo) combinations toward MM cell lines and patient cell samples. A strong synergism of the two nucleoside analogs, when combined at their approximate IC10 concentrations, was observed. This synergism could be partly due to the observed Gem-mediated phosphorylation and activation of deoxycytidine kinase, resulting in enhanced phosphorylation of Gem and Clo. Their cytotoxicity correlated with a robust activation of the DNA damage response pathway. [Gem+Clo] decreased the mitochondrial membrane potential with a concomitant release of proapoptotic factors into the cytoplasm and nucleus and the activation of apoptosis. Exposure of MM cells to [Gem+Clo] also decreased the level of ribosomal RNA (rRNA), which might have resulted in nucleolar stress, as reported previously, and caused a p53-dependent cell death. A reduction by approximately 50% in the cytotoxicity of Gem and Clo was observed in the presence of pifithrin α, a p53 inhibitor. Furthermore, MM cell lines with mutant p53 exhibited greater resistance to Gem and Clo, supporting a role for the p53 protein in these cytotoxic responses. Our results provide a rationale for clinical trials incorporating [Gem+Clo] combinations as part of conditioning therapy for high-risk patients with MM undergoing HSCT.
|Alternate Journal||Exp. Hematol.|