Document Detail


Oleandrin-mediated inhibition of human tumor cell proliferation: importance of Na,K-ATPase alpha subunits as drug targets.
MedLine Citation:
PMID:  19671733     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cardiac glycosides such as oleandrin are known to inhibit the Na,K-ATPase pump, resulting in a consequent increase in calcium influx in heart muscle. Here, we investigated the effect of oleandrin on the growth of human and mouse cancer cells in relation to Na,K-ATPase subunits. Oleandrin treatment resulted in selective inhibition of human cancer cell growth but not rodent cell proliferation, which corresponded to the relative level of Na,K-ATPase alpha3 subunit protein expression. Human pancreatic cancer cell lines were found to differentially express varying levels of alpha3 protein, but rodent cancer cells lacked discernable expression of this Na,K-ATPase isoform. A correlation was observed between the ratio of alpha3 to alpha1 isoforms and the level of oleandrin uptake during inhibition of cell growth and initiation of cell death; the higher the alpha3 expression relative to alpha1 expression, the more sensitive the cell was to treatment with oleandrin. Inhibition of proliferation of Panc-1 cells by oleandrin was significantly reduced when the relative expression of alpha3 was decreased by knocking down the expression of alpha3 isoform with alpha3 siRNA or increasing expression of the alpha1 isoform through transient transfection of alpha1 cDNA to the cells. Our data suggest that the relative lack of alpha3 (relative to alpha1) in rodent and some human tumor cells may explain their unresponsiveness to cardiac glycosides. In conclusion, the relatively higher expression of alpha3 with the limited expression of alpha1 may help predict which human tumors are likely to be responsive to treatment with potent lipid-soluble cardiac glycosides such as oleandrin.
Authors:
Peiying Yang; David G Menter; Carrie Cartwright; Diana Chan; Susan Dixon; Milind Suraokar; Gabriela Mendoza; Norma Llansa; Robert A Newman
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-08-11
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  8     ISSN:  1538-8514     ISO Abbreviation:  Mol. Cancer Ther.     Publication Date:  2009 Aug 
Date Detail:
Created Date:  2009-08-17     Completed Date:  2010-01-19     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2319-28     Citation Subset:  IM    
Affiliation:
Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer, Houston, Texas 77054, USA.
Data Bank Information
Bank Name/Acc. No.:
ClinicalTrials.gov/NCT00554268
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents / metabolism,  pharmacology*
Cardenolides / metabolism,  pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects*
Humans
Mice
Microscopy, Fluorescence
Protein Subunits / analysis,  antagonists & inhibitors*,  metabolism
RNA, Small Interfering
Sodium-Potassium-Exchanging ATPase / analysis,  antagonists & inhibitors*,  metabolism
Transfection
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Cardenolides; 0/Protein Subunits; 0/RNA, Small Interfering; 465-16-7/oleandrin; EC 3.6.1.-/ATP1A1 protein, human; EC 3.6.3.9/Sodium-Potassium-Exchanging ATPase

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