TY - JOUR
T1 - Double-stranded RNA-dependent protein kinase-dependent apoptosis induction by a novel small compound
AU - Hu, Wenxian
AU - Hofstetter, Wayne
AU - Wei, Xiaoli
AU - Guo, Wei
AU - Zhou, Yanbin
AU - Pataer, Abujiang
AU - Li, Hong
AU - Fang, Bingliang
AU - Swisher, Stephen G.
PY - 2009/3
Y1 - 2009/3
N2 - 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 [1H-benzimidazole- 1-ethanol, 2, 3-dihydro-2-imino-a-(phenoxymethyl)-3-(phenylm- ethyl)-, 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.
AB - 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 [1H-benzimidazole- 1-ethanol, 2, 3-dihydro-2-imino-a-(phenoxymethyl)-3-(phenylm- ethyl)-, 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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U2 - 10.1124/jpet.108.141754
DO - 10.1124/jpet.108.141754
M3 - Article
C2 - 19066342
AN - SCOPUS:62449159500
SN - 0022-3565
VL - 328
SP - 866
EP - 872
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 3
ER -