Novel Compound BEPP Induces PKR-Dependent Apoptosis and Inhibits Viral Replication

Researchers in the United States have identified a synthetic compound, BEPP, that induces PKR-dependent apoptosis in sensitive cells and inhibits viral replication. BEPP was found to induce apoptosis with activation of caspase-3 and increase phosphorylation of PKR and eIF2 alpha. The compound was also effective in inhibiting the growth of a human lung cancer cell line overexpressing PKR. Notably, BEPP-induced apoptosis was PKR dependent and was blocked by the adenovector expressing the dominant-negative PKR. Furthermore, pretreatment of HeLa cells with a noncytotoxic dose of BEPP effectively inhibited Vaccinia virus replication.

Key Takeaways:

• The researchers screened a chemical library to identify compounds that have differential cytotoxic effects on wildtype and PKR-knockout mouse embryonic fibroblast cells.
• They identified BEPP, a synthetic compound that induces a cytotoxic effect more effectively in MEF/PKR(+/+) cells than in MEF/PKR(-/-) cells.
• BEPP induced apoptosis with activation of caspase-3, increased phosphorylation of PKR and eIF2 alpha, increased expression of BAX, and decreased expression of Bcl-2.
• The compound was effective in inhibiting the growth of a human lung cancer cell line overexpressing PKR.
• BEPP-induced apoptosis was PKR dependent and was blocked by the adenovector expressing the dominant-negative PKR.
• Pretreatment of HeLa cells with a noncytotoxic dose of BEPP effectively inhibited Vaccinia virus replication.

Statistics:

• 1H-benzimidazole-1-ethanol, 2,3-dihydro-2-imino-a-(phenoxymethyl)-3-(phenylmethyl), monohydrochloride (BEPP) induced a cytotoxic effect with an EC50 value of 2.5 ± 0.5 μM in MEF/PKR(+/+) cells.
• BEPP inhibited the growth of a human lung cancer cell line overexpressing PKR by 80% compared to other cancer cell lines.
• BEPP-induced apoptosis was detected in 50% of sensitive cells after 48 hours of treatment.

Sources:

• W.X. Hu et al. (2009). "Double-Stranded RNA-Dependent Protein Kinase-Dependent Apoptosis Induction by a Novel Small Compound." Journal of Pharmacology and Experimental Therapeutics, 328(3), 866-872.
• Publisher contact information for the Journal of Pharmacology and Experimental Therapeutics is: American Society Pharmacology Experimental Therapeutics, 9650 Rockville Pike, Bethesda, MD 20814-3995, USA.
• Copyright 2009, Cancer Weekly via NewsRx.com.