Double-Stranded RNA-Dependent Protein Kinase-Dependent Apoptosis Induction by a Novel Small Compound
The interferon-induced, double-stranded RNA-dependent protein kinase (PKR) can play critical roles in inhibiting virus replication and inducing apoptosis. To develop new agents that may inhibit viral replication or induce apoptosis in cancer cells via the PKR signaling pathway, we screened a chemica...
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Published in | The Journal of pharmacology and experimental therapeutics Vol. 328; no. 3; pp. 866 - 872 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Pharmacology and Experimental Therapeutics
01.03.2009
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Subjects | |
Online Access | Get full text |
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Summary: | The interferon-induced, double-stranded RNA-dependent protein kinase (PKR) can play critical roles in inhibiting virus replication
and inducing apoptosis. To develop new agents that may inhibit viral replication or induce apoptosis in cancer cells via the
PKR signaling pathway, we screened a chemical library for compounds that have differential cytotoxic effects on wild-type
[mouse embryonic fibroblast (MEF)/PKR(+/+)] and PKR-knockout [MEF/PKR(-/-)] mouse embryonic fibroblast cells. We identified
a synthetic compound, BEPP [1 H -benzimidazole1-ethanol,2,3-dihydro-2-imino- a -(phenoxymethyl)-3-(phenylmethyl)-,monohydrochloride], that induces a cytotoxic effect more effectively in MEF/PKR(+/+) cells
than in MEF/PKR(-/-) cells. BEPP also relatively effectively inhibited the growth of a human lung cancer cell line overexpressing
PKR, compared with other cancer cell lines. In sensitive cells, BEPP induced apoptosis with activation of caspase-3. Treatment
with BEPP led to increased phosphorylation of PKR and eIF2α, increased expression of BAX, and decreased expression of Bcl-2.
BEPP-induced apoptosis was PKR dependent and was blocked by the adenovector expressing the dominant-negative PKR. Furthermore,
pretreatment of HeLa cells at a noncytotoxic dose of BEPP effectively inhibited Vaccinia virus replication. Together, our
results suggest that BEPP and its analogs may induce PKR-dependent apoptosis and inhibition of viral replication and that
they can be a potential anticancer or anti-virus agent. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0022-3565 1521-0103 |
DOI: | 10.1124/jpet.108.141754 |