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Cladribine and bendamustine exhibit inhibitory activity in dexamethasone-sensitive and -resistant multiple myeloma cells.
MedLine Citation:
PMID:  23390564     Owner:  NLM     Status:  PubMed-not-MEDLINE    
Abstract/OtherAbstract:
Cladribine (2-CDA) is a well-known purine nucleoside analog with activities against lymphoproliferative disorders such as hairy cell leukemia (HCL). Bendamustine, a hybrid molecule of purine analog and alkylator, induces apoptosis via DNA damage response and inhibition of mitotic checkpoint. Their therapeutic potential in patients with multiple myeloma (MM), particularly those become resistant to traditional chemotherapeutic agents, remains unclear. Here we study the effects of cladribine or bendamustine on dexamethasone-sensitive (MM1.S) and -resistant (MM1.R) MM cells. MTS-based proliferation assays showed that cladribine and bendamustine exhibited similar anti-proliferation/anti-survival effects on MM1.S and MM1.R cells in a dose-dependent manner. The IC50s of cladribine were approximately 35.3 nmol/L and 58 nmol/L for MM1.S and MM1.R cells, respectively. The IC50s of bendamustine were approximately 119.8 μmol/L (MM1.S) and 138 μmol/L (MM1.R). An apoptotic-ELISA and western blot assays of PARP cleavage and activation of caspase-8 and caspase-3 indicated that cladribine or bendamustine induced apoptosis in both cell lines. Similar results were obtained with flow cytometric analysis showing that cladribine or bendamustine increased the sub-G1 population. Treatment with bendamustine but not cladribine also resulted in cell cycle S-phase arrest. Either cladribine or bendamustine led to a remarkable increase of the phosphorylated H2A.X, CHK1 and CHK2 in both MM1.S and MM1.R cells, suggesting an induction of DNA damage response. Collectively, we demonstrate that cladribine and bendamustine exert potent inhibitory effects on dexamethasone-sensitive and -resistant MM cells in vitro. Our data suggest that MM patients, including those with dexamethasone resistance, may particularly benefit from cladribine or bendamustine.
Authors:
Bo Cai; Shuiliang Wang; Jingcao Huang; Choon-Kee Lee; Chunji Gao; Bolin Liu
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Publication Detail:
Type:  Journal Article     Date:  2013-01-21
Journal Detail:
Title:  American journal of translational research     Volume:  5     ISSN:  1943-8141     ISO Abbreviation:  Am J Transl Res     Publication Date:  2013  
Date Detail:
Created Date:  2013-02-07     Completed Date:  2013-02-08     Revised Date:  2013-05-30    
Medline Journal Info:
Nlm Unique ID:  101493030     Medline TA:  Am J Transl Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  36-46     Citation Subset:  -    
Affiliation:
Department of Hematology, Chinese PLA General Hospital Beijing, China ; Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus Aurora, CO, USA.
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