Biodistribution and Efficacy Studies of the Proteasome Inhibitor BSc2118 in a Mouse Melanoma Model.
Inhibition of the proteasome offers many therapeutic possibilities in inflammation as well as in neoplastic diseases. However, clinical use of proteasome inhibitors is limited by the development of resistance or severe side effects. In our study we characterized the anti-tumor properties of the novel proteasome inhibitor BSc2118. The sensitivity of tumor lines to BSc2118 was analyzed in comparison to bortezomib using crystal violet staining in order to assess cell viability. The In Vivo distribution of BSc2118 in mouse tissues was tracked by a fluorescent-modified form of BSc2118 (BSc2118-FL) and visualized by confocal microscopy. Inhibition of the 20S proteasome was monitored both in cultured cell lines and in mice, respectively. Finally, safety and efficacy of BSc2118 was evaluated in a mouse melanoma model. BSc2118 inhibits proliferation of different tumor cell lines with a similar potency as compared with bortezomib. Systemic administration of BSc2118 in mice is well tolerated, even when given in a dose of 60 mg/kg body weight. After systemic injection of BSc2118 or bortezomib similar proteasome inhibition patterns are observed within the murine organs. Detection of BSc2118-FL revealed correlation of distribution pattern of BSc2118 with inhibition of proteasomal activity in cells or mouse tissues. Finally, administration of BSc2118 in a mouse melanoma model shows significant local anti-tumor effects. Concluding, BSc2118 represents a novel low-toxic agent that might be alternatively used for known proteasome inhibitors in anti-cancer treatment.
Department of Histology and Embryology, Warsaw Medical University, Warsaw, Poland.
Izabela
I
Mlynarczuk-Bialy
Department of Neurology, University of Duisburg-Essen, Essen, Germany.
Thorsten R
TR
Doeppner
Department of Immunology, Warsaw Medical University, Warsaw, Poland.
Jakub
J
Golab
Department of Immunology, Warsaw Medical University, Warsaw, Poland.
Dominika
D
Nowis
Nencki Institute of Experimental Biology, Polish Academy of Science, Warsaw, Poland.
Grzegorz M
GM
Wilczynski
Nencki Institute of Experimental Biology, Polish Academy of Science, Warsaw, Poland.
Kamil
K
Parobczak
Institute of Biochemistry, Charité - Universitätsmedizin, Berlin, Germany.
Moritz E
ME
Wigand
Department of Histology and Embryology, Warsaw Medical University, Warsaw, Poland.
Malgorzata
M
Hajdamowicz
Department of Histology and Embryology, Warsaw Medical University, Warsaw, Poland.
Lukasz P
LP
Biały
Warsaw University of Life Sciences Faculty of Veterinary Medicine Department of Large Animal Diseases with the Clinic Division of Large Animal Internal Diseases, Warsaw, Poland.
Olga
O
Aniolek
Institute of Biochemistry, Charité - Universitätsmedizin, Berlin, Germany.
Petra
P
Henklein
Department of Neurology, University of Goettingen, Goettingen, Germany.
Mathias
M
Bähr
Clemens Schapf Institute for Organic Chemistry and Biochemistry, TU Darmstadt, Darmstadt, Germany.
Boris
B
Schmidt
Institute of Biochemistry, Charité - Universitätsmedizin, Berlin, Germany.
Ulrike
U
Kuckelkorn
Institute of Biochemistry, Charité - Universitätsmedizin, Berlin, Germany.
Peter-M
PM
Kloetzel