Document Detail

Deregulation of apoptotic volume decrease and ionic movements in multidrug-resistant tumor cells: role of chloride channels.
MedLine Citation:
PMID:  19846756     Owner:  NLM     Status:  MEDLINE    
Changes in cell volume and ion gradients across the plasma membrane play a pivotal role in the initiation of apoptosis. Here we explore the kinetics of apoptotic volume decrease (AVD) and ion content dynamics in wild-type (WT) and multidrug-resistant (MDR) Ehrlich ascites tumor cells (EATC). In WT EATC, induction of apoptosis with cisplatin (5 muM) leads to three distinctive AVD stages: an early AVD(1) (4-12 h), associated with a 30% cell water loss; a transition stage AVD(T) ( approximately 12 to 32 h), where cell volume is partly recovered; and a secondary AVD(2) (past 32 h), where cell volume was further reduced. AVD(1) and AVD(2) were coupled to net loss of Cl(-), K(+), Na(+), and amino acids (ninhydrin-positive substances), whereas during AVD(T), Na(+) and Cl(-) were accumulated. MDR EATC was resistant to cisplatin, showing increased viability and less caspase 3 activation. Compared with WT EATC, MDR EATC underwent a less pronounced AVD(1,) an augmented AVD(T), and a delay in induction of AVD(2). Changes in AVD were associated with inhibition of Cl(-) loss during AVD(1), augmented NaCl uptake during AVD(T), and a delay of Cl(-) loss during AVD(2). Application of the anion channel inhibitor NS3728 inhibited AVD and completely abolished the differences in AVD, ionic movements, and caspase 3 activation between WT and MDR EATC. Finally, the maximal capacity of volume-regulated anion channel was found to be strongly repressed in MDR EATC. Together, these data suggest that impairment of AVD, primarily via modulation of NaCl movements, contribute to protection against apoptosis in MDR EATC.
K A Poulsen; E C Andersen; C F Hansen; T K Klausen; C Hougaard; I H Lambert; E K Hoffmann
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Publication Detail:
Type:  Journal Article     Date:  2009-10-21
Journal Detail:
Title:  American journal of physiology. Cell physiology     Volume:  298     ISSN:  1522-1563     ISO Abbreviation:  Am. J. Physiol., Cell Physiol.     Publication Date:  2010 Jan 
Date Detail:
Created Date:  2009-12-18     Completed Date:  2010-01-15     Revised Date:  2010-04-23    
Medline Journal Info:
Nlm Unique ID:  100901225     Medline TA:  Am J Physiol Cell Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  C14-25     Citation Subset:  IM    
Section of Cell- and Developmental Biology, Department of Biology, The August Krogh Bldg., Univ. of Copenhagen, 13 Universitetsparken, DK-2100, Copenhagen ?.
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MeSH Terms
Apoptosis / physiology*
Carrier Proteins / genetics
Cell Cycle
Cell Size
Chloride Channels / physiology*
Cisplatin / therapeutic use
Drug Resistance, Multiple / physiology*
Drug Resistance, Neoplasm
Homeostasis / physiology
Neoplasms / drug therapy
P-Glycoprotein / genetics
Reg. No./Substance:
0/Carrier Proteins; 0/Chloride Channels; 0/P-Glycoprotein; 146313-33-9/betaine plasma membrane transport proteins; 15663-27-1/Cisplatin
Comment In:
Am J Physiol Cell Physiol. 2010 May;298(5):C1276   [PMID:  20413797 ]

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