Inhibitori Hsp90 kao antitumorska terapija

master's thesis

• Title (english): Hsp90 inhibitors as antitumor therapy
• Author: Marko Tomljanović
• Mentor: Sandra Šupraha Goreta (mentor)
• Committee member: Sandra Šupraha Goreta
• Committee member: Olga Gornik
• Committee member: Erim Bešić
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of biochemistry and molecular biology); Zagreb
• Defense date and country: 2015-07-14, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy

Abstract

Hsp90 je evolucijski visoko očuvani molekularni šaperon koji je prisutan u svim prokariotskim i eukariotskim stanicama s izuzetkom arheabakterija. Pripada skupini heat shock proteina, molekularnih šaperona čija je zadaća osigurati pravilno slaganje proteina, sprječavanje nespecifičnih proteinskih interakcija i formiranje proteinskih kompleksa. Hsp90 regulira stabilnost i funkciju više od 200 klijenata, od kojih su brojni uključeni u stanično signaliziranje, regulaciju staničnog ciklusa i staničnog preživljavanja. Klijenti koji su uključeni u navedene procese imaju važnu ulogu i u onkogenezi. Inhibicija Hsp90 rezultira s ubikvitinilacijom i degradacijom navedenih klijenata. Prednost inhibitora Hsp90 pred brojnim drugim kemoterapeuticima je to što se istovremeno postiže oštećenje više signalnih putova koji su od velike važnosti za rast i preživljavanje tumorskih stanica. Inhibicija se postiže spojevima koji se selektivno vežu na vezno mjesto za ATP na N domeni Hsp90 i sprječavaju konformacijske promjene nužne za aktivnost proteina. Monoterapija inhibitorima Hsp90 pokazala je slabe rezultate u liječenju solidnih tumora, međutim kombinacijom inhibitora Hsp90 s drugim citostaticima postigli su se zadovoljavajući rezultati. Trenutno je nekoliko inhibitora Hsp90 u 2. i 3. fazi kliničkih ispitivanja za liječenje karcinoma pluća nemalih stanica, HER2+ tumora dojke i multiplog mijeloma. Budućnost liječenja tumora s inhibitorima Hsp90 temeljiti će se na njihovom kombiniranju s ostalim citostaticima, pri čemu se postiže sinergistički učinak.

Abstract (english)

Hsp90 is highly evolutionary conserved molecular chaperone who is present in all prokaryotic and eukaryotic cells, with the exception of arheabacteria. It belongs to a group of heat shock proteins, molecular chaperons whose function is to secure correct protein folding, preventing unspecific protein interactions and forming protein complexes. Hsp90 regulates the stability and function of more than 200 clients, many of which are included in cellular signalling, regulation of cell cycle and cell survival. Clients who are involved in these processes also have important role in oncogenesis. Inhibition of Hsp90 results in ubiquitinilation and degradation of mentioned clients. Advantage of Hsp90 inhibitors over many other chemotherapeutics is that they accomplish simultaneous disruption of multiple signalling pathways that are of great importance for growth and survival of cancer cells. Inhibition is accomplished by compounds that selectively bind to the ATP binding spot in N domain of Hsp90 and prevent conformational changes that are necessary for protein activity. Hsp90 monotherapy showed weak results in treatment of solid tumors, however combining Hsp90 inhibitors with other cytostatic drugs showed satisfying results. At the moment there are couple of Hsp90 inhibitors in 2nd and 3rd phase of clinical trials for treatment of non-small cell lung cancer, HER2+ breast cancer and multiple myeloma. The future of tumor treatment with Hsp90 inhibitors will be based on combining them with other cytostatics, which results in synergistic effect.

• Keywords: tumor; proteini toplinskog šoka; Hsp90 inhibitori; antitumorska terapija
• Keywords (english): tumor; heat shock proteins; Hsp90 inhibitors; antitumor therapy
• Language: croatian
• URN:NBN: urn:nbn:hr:163:815199
• Study programme: Title: Pharmacy; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: magistar/magistra farmacije (magistar/magistra farmacije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Access restricted to students and staff of home institution
• Created on: 2016-01-20 14:53:03