Selective cytotoxicity of amidinopiperidine based compounds towards burkittʼs lymphoma cells involves proteasome inhibition
Gobec, Martina (Author), Obreza, Aleš (Author), Prijatelj, Matevž (Author), Brus, Boris (Author), Gobec, Stanislav (Author), Mlinarič-Raščan, Irena (Author)

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Serine proteases have proven to be promising pharmacological targets in contemporary drug discovery for cancer treatment. Since azaphenylalanine-basedcompounds 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 mM range, with IC50 18 mM and 22 mM 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 thepro-survival pathway in Burkittʼs lymphoma through NFkB inhibition. The accumulation of phosphorylated precursor (p105) and inhibitory (IkB) molecules with no subsequent release of active NFkB 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.

Keywords:serinske proteaze, tarčna farmakologija, rak, zdravljenje, aminopepiridin, Burkitt limfne celice, kemoterapija, Ramos celice
Work type:Not categorized (r6)
Tipology:1.01 - Original Scientific Article
Organization:FFA - Faculty of Pharmacy
Number of pages:art. no. e41961 (12 str.)
Numbering:Vol. 7, no. 7
DOI:10.1371/journal.pone.0041961 Link is opened in a new window
COBISS.SI-ID:3286129 Link is opened in a new window
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