Mehanizmi djelovanja fenolnih kiselina na oksidacijski stres, polarizaciju makrofaga, angiogenezu i rast Ehrlichova ascitesnoga tumora

doctoral thesis

• Title (english): The mechanisms of phenolic acids action on oxidative stress, polarization of macrophages, angiogenesis and Ehrlich ascites tumor growth
• Author: Martina Kunštić
• Mentor: Nada Oršolić (mentor)
• Committee member: Domagoj Đikić (predsjednik povjerenstva)
• Committee member: Sandra Radić Brkanac (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Biology); Zagreb
• Defense date and country: 2018, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Biology
• Universal decimal classification (UDC): 57 - Biological sciences. Physical anthropology. Biodiversity

Abstract

Angiogeneza, proces nastanka krvožilja, zajedno s upalom ključna je za rast i metastaziranje raka. Novačenje makrofaga te produkcija citokina/kemokina, čimbenika rasta i proteolitičkih enzima je zajednička karakteristika upale, angiogeneze i raka, te važan cilj novog pristupa liječenja raka. Fenolne kiseline (galna, kafeinska i taninska kiselina) kao prirodne fitokemikalije i snažni antioksidansi pokazuju kemopreventivna i terapijska svojstva u liječenju raka. Istražili smo učinak fenolnih kiselina na rast tumora, angiogenezu, polarizaciju makrofaga i oksidacijski stres na modelu angiogeneze prouzročene ip unosom EAT stanica (2,5x106) u Swiss albino miša. Rezultati pokazuju da fenolne kiseline pokazuju imunostimulatorni, protuupalni, antiangiogeni i protutumorski učinak. Protutumorski učinak fenolnih kiselina temelji se na citotoksičnoj djelotvornosti M1 makrofaga, izravnoj inhibiciji rasta EAT stanica, inhibiciji čimbenika rasta krvožilnog endotela (VEGF) te rasta krvožilja u peritonealnoj šupljini miševa nositelja EAT. Fenolne kiseline kroz inhibiciju produkcije proangiogenih čimbenika, posebice VEGF čimbenika, metaloproteinaza 2 i 9 (MMP-2 i MMP-9) te aktivnosti ciklooksigenaze 2 (COX-2), inhibiraju proces angiogeneze, rast tumora i povećavaju preživljenje miševa nositelja EAT stanica. Antioksidativna sposobnost fenolnih sastavnica blokira pojavnost M2 tumoru pridruženih makrofaga (TAMs) i značajno inhibira tumorogenezu u mišjem modelu. Temeljem navedenog, inhibicija TAMs može biti učinkovita u liječenju tumora i drugih kroničnih bolesti povezanih s procesom angiogeneze.

Abstract (english)

Angiogenesis, the process of formation of blood vessels, together with inflammation, is essential for tumor growth and metastasis. Macrophage recruitment and cytokine/chemokine production, growth factors and proteolytic enzymes is a common feature of inflammation, angiogenesis and cancer, and an important goal of a new approach to cancer treatment. Phenolic acids (gallic, caffeic and tannic acid) as natural phytochemicals and strong antioxidants show chemopreventive and therapeutic properties in cancer treatment. We investigated the effect of phenolic acids on tumor growth, angiogenesis, macrophage polarization and oxidative stress on the angiogenic model caused by ip inoculation of EAT cells (2.5x106) in Swiss albino mouse. The results show that phenolic acids exhibit immunostimulatory, anti-inflammatory, antiangiogenic and antitumor effects. The antitumor effect of phenolic acids is based on the cytotoxic efficacy of M1 macrophage, direct inhibition of EAT cell growth, inhibition of vascular endothelial growth factors (VEGF) and growth of blood vessels in the peritoneal cavity of EAT-bearing mice. Phenolic acids through the inhibition of proangiogenic factors, particularly VEGF, metalloproteinases 2 and 9 (MMP-2 and MMP-9) and cyclooxygenase 2 activity (COX-2), inhibit process of angiogenesis, tumor growth and increase survival of EAT-bearing mice. The antioxidant ability of phenolic components blocks the occurrence of M2 tumor associated macrophages (TAMs) and significantly inhibits tumorigenesis in mouse model. Based on the above, TAMs inhibition may be effective in the cancer treatment and other chronic diseases associated with process of angiogenesis.

• Keywords: angiogeneza; fenolne kiseline; oksidacijski stress; polarizacija makrofaga; proangiogeni čimbenici; TAMs
• Keywords (english): angiogenesis; phenolic acids; oxidative stress; macrophage polarization; proangiogenic factors; TAMs
• Language: croatian
• URN:NBN: urn:nbn:hr:217:363228
• Study programme: Title: Biology; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje prirodnih znanosti, polje biologija (doktor/doktorica znanosti, područje prirodnih znanosti, polje biologija)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access; Embargo expiration date: 2020-03-16
• Created on: 2018-04-06 10:35:32