Document Detail

A mechanism for P-glycoprotein-mediated apoptosis as revealed by verapamil hypersensitivity.
MedLine Citation:
PMID:  14567677     Owner:  NLM     Status:  MEDLINE    
Selection of tumor cell lines with anticancer drugs has led to the appearance of multidrug-resistant (MDR) subclones with P-glycoprotein 1 (P-gp1) expression. These cells are cross-resistant to several structurally and functionally dissimilar drugs. Interestingly, in the process of gaining resistance, MDR cells become hypersensitive or collaterally sensitive to membrane-active agents, such as calcium channel blockers, steroids, and local anaesthetics. In this report, hypersensitivity to the calcium channel blocker, verapamil, was analyzed in sensitive and resistant CHO cell lines. Our results show that treatment with verapamil preferentially induced apoptosis in MDR cells compared to drug-sensitive cells. This effect was independent of p53 activity and could be inhibited by overexpression of the Bcl-2 gene. The induction of apoptosis by verapamil had a biphasic trend in which maximum cell death occurred at 10 microM, followed by improved cell survival at higher concentrations (50 microM). We correlated this effect to a similar biphasic trend in P-gp1 ATPase activation by verapamil in which low concentrations of verapamil (10 microM) activated ATPase, followed by inhibition at higher concentrations. To confirm the relationship between apoptosis and ATPase activity, we used two inhibitors of P-gp1 ATPase, PSC 833 and ivermectin. These ATPase inhibitors reduced hypersensitivity to verapamil in MDR cells. In addition, low concentrations of verapamil resulted in the production of reactive oxygen species (ROS) in MDR cells. Taken together, these results show that apoptosis was preferentially induced by P-gp1 expressing cells exposed to verapamil, an effect that was mediated by ROS, produced in response the high ATP demand by P-gp1.
Joel Karwatsky; Maximilian C Lincoln; Elias Georges
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Biochemistry     Volume:  42     ISSN:  0006-2960     ISO Abbreviation:  Biochemistry     Publication Date:  2003 Oct 
Date Detail:
Created Date:  2003-10-21     Completed Date:  2003-12-02     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0370623     Medline TA:  Biochemistry     Country:  United States    
Other Details:
Languages:  eng     Pagination:  12163-73     Citation Subset:  IM    
Institute of Parasitology, McGill University, Macdonald Campus, Ste-Anne de Bellevue, Quebec H9X 3V9, Canada.
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MeSH Terms
Adenosine Triphosphatases / antagonists & inhibitors,  metabolism
Apoptosis / physiology*
CHO Cells
Cell Line, Tumor
Drug Resistance, Multiple
Enzyme Activation
Flow Cytometry
P-Glycoprotein / antagonists & inhibitors,  physiology*
Verapamil / pharmacology*
Reg. No./Substance:
0/P-Glycoprotein; 52-53-9/Verapamil; EC 3.6.1.-/Adenosine Triphosphatases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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