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ToxSci Advance Access published online on May 2, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg052
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received December 5, 2002; accepted January 27, 2003
© 2003 Society of Toxicology

Immunotoxicology

Reversal of Bcl-2-Mediated Resistance of the EW36 Human B-Cell Lymphoma Cell Line to Arsenite- and Pesticide-Induced Apoptosis by PK11195, a Ligand of the Mitochondrial Benzodiazepine Receptor

Donna E. Muscarella 1*, Kerry A. O'Brien 1, Ann T. Lemley 2, Stephen E. Bloom 1

1 Department of Microbiology and Immunology, Cornell University, Ithaca, New York 14853; Institute for Comparative and Environmental Toxicology, Cornell University, Ithaca, New York 14853
2 Department of Textiles and Apparel, Cornell University, Ithaca, New York 14853; Institute for Comparative and Environmental Toxicology, Cornell University, Ithaca, New York 14853

* To whom correspondence should be addressed. E-mail: dem10{at}cornell.edu.


  Abstract

Opening of the permeability transition (PT) pore is a central feature of apoptosis induction by chemical stress. One component of the PT pore, the mitochondrial benzodiazepine receptor (mBzR), has recently received attention for its potential role in modulating PT pore function. Specifically, antagonistic ligands of the mBzR, such as 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxamide (PK11195), have been shown to sensitize Bcl-2 overexpressing cells to apoptosis induction by facilitating the opening of the PT pore and the subsequent loss of mitochondrial membrane potential ({Delta}{psi}m). We examined whether PK11195 can sensitize EW36, a human B-cell lymphoma cell line that over-expresses Bcl-2, to apoptosis induction and mitochondrial depolarization by environmental chemicals including mitochondrial toxicants. We found that, although EW36 cells are refractory to apoptosis induction by antimycin A, rotenone, pyridaben, alachlor, and carbonyl cyanide m-chlorophenylhydrazone (mClCCP), they are dramatically sensitized to induction of apoptosis by low concentrations of these same agents following pre-treatment with PK11195. The sensitization of EW36 cells is accompanied by a rapid and extensive loss of {Delta}{psi}m within a few hours following chemical exposure. Furthermore, using sodium arsenite, we examined the role of the c-Jun N-terminal kinase (JNK) pathway and protein synthesis in apoptosis induction in EW36. We found that, unlike untreated cells, EW36 cells treated with PK11195 no longer show an association of JNK pathway activation with apoptosis induction. Importantly, PK11195 eliminates a requirement for protein synthesis in chemically induced apoptosis in EW36 cells. These results show significant drug-mediated alteration of cell sensitivity and JNK pathway activation to environmental chemicals and mitochondrial toxicants, following ligation of the mBzR.

Key Words: apoptosis, c-Jun N-terminal kinase, arsenite, pesticide, B-lymphocyte, PK11195 .


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