Azaphenylalanine-based serine protease inhibitors induce caspase-mediated apoptosis.
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 (K(i)) in the nanomolar range. However, they could also inhibit at least one additional serine protease (trypsin, chymotrypsin and/or coagulation factor X) with K(i) values in the nanomolar or low micromolar range. These serine protease inhibitors constitute novel apoptosis inducing compounds in B-cell lymphoma cells.
Celhar
Teja
T
University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia.
Batista Napotnik
Tina
T
Obreza
Ales
A
Zega
Anamarija
A
Anderluh
Petra Stefanic
PS
Kikelj
Danijel
D
Mlinaric-Rascan
Irena
I
D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D016393:Lymphoma, B-Cell / Q000378:metabolism / Q000473:pathology; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013997:Time Factors
D015842:Serine Proteinase Inhibitors; C493947:azaphenylalanine; D010649:Phenylalanine; D020169:Caspases