TY - JOUR
T1 - Mechanistic studies on the synergistic cytotoxicity of the nucleoside analogs gemcitabine and clofarabine in multiple myeloma
T2 - Relevance of p53 and its clinical implications
AU - Valdez, Benigno C.
AU - Wang, Guiyun
AU - Murray, David
AU - Nieto, Yago
AU - Li, Yang
AU - Shah, Jatin
AU - Turturro, Francesco
AU - Wang, Michael
AU - Weber, Donna M.
AU - Champlin, Richard E.
AU - Qazilbash, Muzaffar H.
AU - Andersson, Borje S.
N1 - Funding Information:
This work was supported in part by a grant from the National Institutes of Health (CCSG Core CA16672 ), and The Stephen L. and Lavinia Boyd Fund for Leukemia Research.
PY - 2013/8
Y1 - 2013/8
N2 - 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.
AB - 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.
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U2 - 10.1016/j.exphem.2013.04.009
DO - 10.1016/j.exphem.2013.04.009
M3 - Article
C2 - 23648290
AN - SCOPUS:84880755309
SN - 0301-472X
VL - 41
SP - 719
EP - 730
JO - Experimental Hematology
JF - Experimental Hematology
IS - 8
ER -