hrvatski

Proteini toplinskog stresa kao mete antitumorske terapije

Proteini toplinskog stresa (stresni proteini, engl. heat shock proteins, Hsp) jesu proteini konzerviranog aminokiselinskoga slijeda, konstitutivno prisutni u stanicama u fiziološkim uvjetima, a inducirani u uvjetima stresa toplinski stres ili druge vrste stresa uzrokovanih prisutnošću analoga aminokiselina, teških metala, reaktivnih kisikovih spojeva, citotoksičnih agensa), bakterijskih ili virusnih infekcija. Hsp igraju kritičnu ulogu u održavanju homeostaze, prvenstveno regulacijom putova stanične proliferacije, apoptoze ili transporta proteina, a kao šaperoni sudjeluju u strukturiranju staničnih proteina. U stanicama različitih vrsta tumora nađene su povišene koncentracije Hsp-a s kojima se povezuje otpornost na antitumorsku terapiju i metastaziranje tumora. S obzirom da Hsp70 i Hsp90 reguliraju apoptozu, bilo da se radi o apoptozi ovisnoj o mitohondrijima ili apoptozi potaknutoj vezanjem liganda na receptore smrti, ispitivani su antitumorski učinci inhibicije Hsp70 i Hsp90 na dvo- i tro-dimenzionalnim staničnim modelima. Hsp70 je inhibiran uporabom male interventne RNA (siRNA) pri čemu je siRNA za hsp70 mRNA dostavljana u stanice uklopljena u kitozanske nanočestice, a Hsp90 je inhibiran celastrolom. Inhibicija Hsp70 i Hsp90, pojedinačno i skupno, prouzročila je značajno smanjenje vijabilnosti tumorskih stanica. Zaključno, rezultati ovog istraživanja sugeriraju: a) da su stresni proteini kao regulatori apoptoze atraktivne mete antitumorske terapije, b) da je RNA interferencija moćni alat za regulaciju ekspresije gena koji bi se mogao koristiti u terapijske svrhe te c) da nanočestice imaju veliki potencijal u dostavi antitumorskih agensa u stanicu. Heat shock proteins (Hsp) are conserved proteins, constitutively expressed in cells under physiological conditions, but induced under stress conditions (heat shock or other kinds of stress caused by the presence of amino acid analogues, heavy metals, reactive oxygen species, cytotoxic agents), bacterial or viral infections. Hsp play a critical role in the maintenance of homeostasis by regulating cell proliferation, apoptosis, protein folding and transport. Malignant cells are characterized by an increased concentration of Hsp which is related to their resistance to anti-cancer therapy and their ability to metastasise. Because Hsp70 and Hsp90 regulate apoptosis, antitumor effects of inhibition of Hsp70 and Hsp90 in two-and three-dimensional cell models were examined. Hsp70 was inhibited by siRNA interference using siRNA for hsp70 mRNA which was delivered into the cells with chitosan based nanoparticles. Hsp90 is inhibited by celastrol. Inhibition of Hsp70 and/or Hsp90 caused a significant reduction of cell viability. In conclusion, the results of this study suggest that: a) Hsp, as regulators of apoptosis, are attractive targets for antitumor therapy, b) that RNA interference is a powerful tool for posttranscriptional silencing of genes, and c) that nanoparticles have great potential to deliver antitumor agents.

proteini toplinskoga stresa; Hsp70; apoptooza; siRNMA; nanoterapija;

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