Erciyes Üniversitesi Fen Bilimleri Enstitüsü Fen Bilimleri Dergisi 1012-2354 Erciyes Üniversitesi Kanser tedavisinde proteozom inhibitörlerinin önemi The importance of proteasome inhibitors in cancer therapy Engür Selin ANADOLU ÜNİVERSİTESİ, SAĞLIK BİLİMLERİ ENSTİTÜSÜ, FARMAKOLOJİ ANABİLİM DALI Dikmen Miriş Anadolu Üniversitesi, Eczacılık Fakültesi, Farmakoloji Anabilim Dalı, Eskişehir, Türkiye 08 01 2015 31 4 182 190 08 01 2015 Copyright © 1985, Erciyes Üniversitesi Fen Bilimleri Enstitüsü Fen Bilimleri Dergisi 1985 Erciyes Üniversitesi Fen Bilimleri Enstitüsü Fen Bilimleri Dergisi

Son yıllarda ubikütin-proteozom sistemi, hücre büyümesi ve ölümü arasında denge, insan malignansilerinin ilerlemesi ve kanser hücrelerindeki ilaç direnci gelişimi gibi mekanizmalar için gerekli olarak tanımlanmıştır. Proteozom fonksiyonunun inhibisyonu, anti-kanser terapi için güçlü bir strateji olarak ortaya çıkmıştır. Proteozom’un klinik olarak doğrulanmasının ardından ilk proteozom inhibitörü olan bortezomib, malignant hastalıkların tedavisinde kullanılmaya başlanmış ve farmakolojik olarak geliştirilmiş olan ikinci nesil proteozom inhibitörlerinin keşfedilmesini hızlandırmıştır. Ixazomib, delanzomib, oprozomib ve marizomib gibi ikinci nesil proteozom inhibitörleri, son zamanlarda geliştirilmiş ve klinik olarak test edilmeye başlanmıştır. Bu makale, kanserde terapötik ajan olan proteozom inhibitörinin özelliklerini, yeni nesil proteozom inhibitörlerinin klinikteki ilerlemelerini ve proteozom inhibitörlerinin temel mekanizmasını özellikle NF-?B inhibisyonu yönünden özetlemektedir.

In recent years the ubiquitin–proteasome system has been identified as essential for maintaining a important balance between cell growth and death, the progression of human malignancies, and the development of drug resistance in cancer. Inhibition of proteasome function has emerged as strong strategy for anti-cancer therapy. Clinical confirmation of the proteasome as a therapeutic target was achieved with bortezomib which is the first proteasome inhibitor to be implemented in the treatment of malignant disease and has prompted the development of a second generation of proteasome inhibitors with improved pharmacological properties. Other novel proteasome inhibitors, such as ixazomib, delanzomib, oprozomib and marizomib, have recently been developed and are being tested in clinical trials. This review summarises the main mechanisms of action of proteasome inhibitors in cancer especially inhibition of NF-?B, the development of proteasome inhibitors as therapeutic agents and the properties and progress of next generation proteasome inhibitors in the clinic.

 Bortezomib cancer NF-κB Proteasome inhibitor Bortezomib Kanser NF-κB proteozom inhibitörleri Adams, J., Behnke, M., Chen, S., Potent and selective inhibitors of the proteasome: dipeptidyl boronic acids, Bioorg. Med. Chem. Lett., 8, 333-8, 1998.Aussie, L.K., Francis, F., Gengler, N., Haubruge, E., 2007. Response and genetic analysis of malathion-specific resistant Tribolium castaneum (Herbst) in relation to population density. J. Stored Prod. Res. 43 (1), 33-44. Aghajanian, C., Soignet, S., Dizon, D.S., A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies, Clin. Cancer Res. 8, 2505–2511, 2002. Aghajanian, C., Soignet, S., Dizon, D.S., A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies, Clin. Cancer Res. 8, 2505–2511, 2002. Allegra A., Alonci A., Gerace D., Russo S., Innao V., Calabrò L., Musolino C., New orally active proteasome inhibitors in multiple myeloma, Leukemia Research, 38, 1-9, 2014. Almond, J.B., Cohen, G.M., The proteasome: a novel target for cancer chemotherapy, Leukemia, 16, 433-43, 2002. Anderson, K.C., The 39th David A. Karnofsky Lecture: bench-to-bedside translation of targeted therapies in multiple myeloma, J. Clin. Oncol., 30, 445-452, 2012. Brüning, A., Vogel, M., Mylonas, I., Friese, K., Burges, A., Bortezomib targets the caspase-like proteasome activity in cervical cancer cells, triggering apoptosis that can be enhanced by Nelfinavir, Curr. Cancer Drug Targets, 2011. Cardoso, F., Durbecq, V., Laes, J.F., Badran, B., Lagneaux, L., Bex, F., Desmedt, C., Willard-Gallo, K., Ross, J.S., Burny, A., Bortezomib (PS-341, Velcade) increases the efficacy of trastuzumab (Herceptin) in HER-2-positive breast cancer cells in a synergistic manner, Mol. Cancer Ther., 5, 3042-3051, 2006. Chauhan, D., Tian, Z., Zhou, B., Kuhn, D.J., Orlowski, R.Z., Raje, N.S., Richardson, P.G., Anderson, K.C., In vitro and in vivo selective antitumor activity of a novel orally bioavailable proteasome inhibitor MLN9708 against multiple myeloma cells, Clin. Cancer Res., 17, 5311–5321, 2011. Cooper, M.G., Hausman, R.E., Hücre, Moleküler Yaklaşım, İzmit Tıp Kitap Evi, İzmir, 631-673, 2006. Dick, L.R., Fleming, P.E., Building on bortezomib: second- generation proteasome inhibitors as anti-cancer therapy, Drug Discovery Today, 15, 5-6, 2010. Dou Q. P., Zonder J. A., Overview of Proteasome Inhibitor- Based Anti-cancer Therapies: Perspective on Bortezomib and Second Generation Proteasome Inhibitors versus Future Generation Inhibitors of Ubiquitin-Proteasome System, Current Cancer Drug Targets, 14, 517-536, 2014. Dutaud, D., Aubry, L., Henry, L., Levieux, D., Hendil, K.B., Kuehn, L., Bureau, J.P. and Ouali, A., Development and evaluation of a sandwich ELISA for quantification of the 20S proteasome in human plasma, J.Immunol. Methods., 260, 183-93, 2002.