Therapeutic potential of cladribine in combination with STAT3 inhibitor against multiple myeloma

BMC Cancer

Research Article

Xin-Sheng Deng¹  Shuiliang Wang¹  Bolin Liu¹  Xiao-Dan Yu²  Ming Zhao²  Jian Ma³  Choon-Kee Lee⁴ 

[1] Department of Pathology, University of Colorado Anschutz Medical Campus School of Medicine, Aurora, CO, USA;Department of Stress Medicine, Institute of Basic Medical Sciences, Beijing, P.R. China;International Medical Centre of PLA General Hospital, Beijing, P.R. China;The Myeloma and Amyloidosis Program, Department of Medicine, University of Colorado Anschutz Medical Campus School of Medicine, Aurora, CO, USA;

关键词: Multiple Myeloma;    U266 Cell;    Cladribine;    Hairy Cell Leukemia;    PARP Cleavage;   

DOI  :  10.1186/1471-2407-11-255

 received in 2011-02-04, accepted in 2011-06-16,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundCladribine or 2-chlorodeoxyadenosine (2-CDA) is a well-known purine nucleoside analog with particular activity against lymphoproliferative disorders, such as hairy cell leukemia (HCL). Its benefits in multiple myeloma (MM) remain unclear. Here we report the inhibitory effects of cladribine on MM cell lines (U266, RPMI8226, MM1.S), and its therapeutic potential in combination with a specific inhibitor of the signal transducer and activator of transcription 3 (STAT3).MethodsMTS-based proliferation assays were used to determine cell viability in response to cladribine. Cell cycle progression was examined by flow cytometry analysis. Cells undergoing apoptosis were evaluated with Annexin V staining and a specific ELISA to quantitatively measure cytoplasmic histone-associated DNA fragments. Western blot analyses were performed to determine the protein expression levels and activation.ResultsCladribine inhibited cell proliferation of MM cells in a dose-dependent manner, although the three MM cell lines exhibited a remarkably different responsiveness to cladribine. The IC50 of cladribine for U266, RPMI8226, or MM1.S cells was approximately 2.43, 0.75, or 0.18 μmol/L, respectively. Treatment with cladribine resulted in a significant G1 arrest in U266 and RPMI8226 cells, but only a minor increase in the G1 phase for MM1.S cells. Apoptosis assays with Annexin V-FITC/PI double staining indicated that cladribine induced apoptosis of U266 cells in a dose-dependent manner. Similar results were obtained with an apoptotic-ELISA showing that cladribine dramatically promoted MM1.S and RPMA8226 cells undergoing apoptosis. On the molecular level, cladribine induced PARP cleavage and activation of caspase-8 and caspase-3. Meanwhile, treatment with cladribine led to a remarkable reduction of the phosphorylated STAT3 (P-STAT3), but had little effect on STAT3 protein levels. The combinations of cladribine and a specific STAT3 inhibitor as compared to either agent alone significantly induced apoptosis in all three MM cell lines.ConclusionsCladribine exhibited inhibitory effects on MM cells in vitro. MM1.S is the only cell line showing significant response to the clinically achievable concentrations of cladribine-induced apoptosis and inactivation of STAT3. Our data suggest that MM patients with the features of MM1.S cells may particularly benefit from cladribine monotherapy, whereas cladribine in combination with STAT3 inhibitor exerts a broader therapeutic potential against MM.

【 授权许可】

Unknown   
© Ma et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.