Document Detail

Reduced expression of Rho guanine nucleotide dissociation inhibitor-alpha modulates the cytotoxic effect of busulfan in HEK293 cells.
MedLine Citation:
PMID:  17264767     Owner:  NLM     Status:  MEDLINE    
High-dose busulfan is an important component in many conditioning protocols for hematopoietic stem cell or bone marrow transplantation. Treatment with busulfan results in the inhibition of cell cycle progression and apoptosis of tumor cells. As Rho GTPases are involved in cell cycle regulation, we investigated the influence of modified Rho guanine nucleotide dissociation inhibitor-alpha (GDI), a physiological inhibitor of Rho GTPases, on busulfan activity in cancer cells. RhoGDIalpha has been shown to be overexpressed in multiple types of tumors such as ovarian and breast cancer. To investigate the role of RhoGDIalpha, we established a RhoGDIalpha knockdown by the transient transfection of HEK293 cells with specific small interfering RNA resulting in strongly reduced RhoGDIalpha mRNA and protein expression. Other members of the RhoGDI family such as RhoGDIbeta and RhoGDIgamma were not affected. In RhoGDIalpha knockdown cells, cell cycle regulation was not altered by the downregulation of RhoGDIalpha; however, the rate of apoptotic cells increased when compared with the control small interfering RNA-transfected cells. In addition, treatment of cells with busulfan resulted in a further increased apoptotic rate, as determined by fluorescence-activated cell sorter analysis and caspase-3 activation. Such a sensitization of RhoGDIalpha small interfering RNA transfected cells was also found upon treatment with doxorubicin and taxol. In summary, we could demonstrate that the expression of RhoGDIalpha influences the sensitivity of cells toward busulfan-induced cytotoxicity.
Janka Reimer; Sandra Bien; Jürgen Sonnemann; James F Beck; Thomas Wieland; Heyo K Kroemer; Christoph A Ritter
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Anti-cancer drugs     Volume:  18     ISSN:  0959-4973     ISO Abbreviation:  Anticancer Drugs     Publication Date:  2007 Mar 
Date Detail:
Created Date:  2007-01-31     Completed Date:  2007-04-17     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9100823     Medline TA:  Anticancer Drugs     Country:  England    
Other Details:
Languages:  eng     Pagination:  333-40     Citation Subset:  IM    
Department of Pharmacology, Research Center of Pharmacology and Experimental Therapeutics, Ernst Moritz Arndt University, Greifswald, Germany.
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MeSH Terms
Antineoplastic Agents, Alkylating / pharmacology*
Blotting, Western
Busulfan / pharmacology*
Caspase 3 / biosynthesis
Cell Line, Tumor
Down-Regulation / drug effects
Drug Synergism
Enzyme Induction / drug effects
Fluorescent Antibody Technique
Guanine Nucleotide Dissociation Inhibitors / biosynthesis*
RNA, Neoplasm / biosynthesis
RNA, Small Interfering
Spectrometry, Fluorescence
rho GTP-Binding Proteins / metabolism
Reg. No./Substance:
0/Antineoplastic Agents, Alkylating; 0/Guanine Nucleotide Dissociation Inhibitors; 0/RNA, Neoplasm; 0/RNA, Small Interfering; 133312-85-3/rho guanine nucleotide dissociation inhibitors; 55-98-1/Busulfan; EC 3.4.22.-/Caspase 3; EC GTP-Binding Proteins

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