Molecules regulating cell death constitute prominent therapeutic targets. The pro-apoptotic role of serine protease inhibitors prompted us to search for novel modulators of this process. We have ...tested some recently synthesized antithrombotic compounds for their potential to induce apoptotic cell death. Cell based analyses revealed that inhibitors built on the azaphenylalanine scaffold are, for B-cell lymphoma cells, severely cytotoxic, while other compounds tested were moderate or non-cytotoxic. These inhibitors induced the time and concentration dependent biochemical and morphological characteristics of apoptosis, such as DEVDase activation, loss of mitochondrial membrane potential, nuclear degradation and genomic DNA fragmentation. Most of the inhibitors proved to be selective for thrombin, with inhibition constants (Ki) in the nanomolar range. However, they could also inhibit at least one additional serine protease (trypsin, chymotrypsin and/or coagulation factor X) with Ki values in the nanomolar or low micromolarrange. These serine protease inhibitors constitute novel apoptosis inducing compounds in B-cell lymphoma cells.
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