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Biochemistry - Hematology - Oncology

Selective Cytotoxicity of Amidinopiperidine Based Compounds Towards Burkitt’s Lymphoma Cells Involves Proteasome Inhibition
Published: Monday, July 30, 2012
Author: Martina Gobec et al.

by Martina Gobec, Ales Obreza, Matevz Prijatelj, Boris Brus, Stanislav Gobec, Irena Mlinaric-Rascan

Serine proteases have proven to be promising pharmacological targets in contemporary drug discovery for cancer treatment. Since azaphenylalanine-based compounds manifest cytotoxic activity, we have selected serine protease inhibitors designed and synthesized in-house with large hydrophobic naphthalene moiety for screening. The cytotoxic potential of screened molecules was correlated to modifications of R1 residues. The most cytotoxic were compounds with greater basicity; amidinopiperidines, piperidines and benzamidines. Amidinopiperidine-based compounds exert cytotoxicity in low µM range, with IC50 18 µM and 22 µM for inhibitors 15 and 16 respectively. These compounds exhibited selective cytotoxicity towards the Burkitt’s lymphoma cells Ramos and Daudi, and proved nontoxic to PMBC, Jurkat and U937. They induce caspase-dependent apoptotic cell death, as demonstrated by the use of a pan-caspase inihibitor, zVADfmk, which was able to rescue Ramos cells from compound(s)-induced apoptosis. We confirm a disruption of the pro-survival pathway in Burkitt’s lymphoma through NF?B inhibition. The accumulation of phosphorylated precursor (p105) and inhibitory (I?B) molecules with no subsequent release of active NF?B implicated the involvement of proteasome. Indeed, we show that the amidinopiperidine-based compounds inhibit all three proteolytical activities of the human 20S proteasome, with the most prominent effect being on the trypsin-like activity. Consistently, treatment of Ramos cells with these compounds led to an increase in ubiquitinated proteins. The amidinopiperidine-based serine protease inhibitors presented are, as selective inducers of apoptosis in Burkitt’s lymphoma cells, promising leads for the development of novel chemotherapeutics.