Comparative toxicity evaluation of targeted anticancer therapeutics in embryonic zebrafish and sea urchin models
2018
Autori:
Babić, TamaraDinić, Jelena
Stojković Burić, Sonja
Hadzic, Stefan
Pešić, Milica
Radojković, Dragica
Divac Rankov, Aleksandra
Tip dokumenta:
Članak u časopisu (Recenzirana verzija)
,
© 2018 Akadémiai Kiadó, Budapest
Metapodaci
Prikaz svih podataka o dokumentuApstrakt:
Cancer drug resistance and poor selectivity towards cancer cells demand the constant search for new therapeutics. PI3K-Akt-mTOR and RAS-MAPK-ERK signaling pathways are key mechanisms involved in cell survival, proliferation, differentiation, and metabolism and their deregulation in cancer can promote development of therapy resistance. We investigated the effects of targeted inhibitors (wortmannin, GSK690693, AZD2014 and tipifarnib) towards these two pathways on early zebrafish and sea urchin development to assess their toxicity in normal, fast proliferating cells. PI3K inhibitor wortmannin and RAS inhibitor tipifarnib displayed highest toxicity while GSK690693, a pan-Akt kinase inhibitor, exhibited a less significant impact on embryo survival and development. Moreover, inhibition of the upstream part of the PI3K-Akt-mTOR pathway (wortmannin/GSK690693 co-treatment) produced a synergistic effect and impacted zebrafish embryo survival and development at much lower concentrations. Dual mTORC1/mTORC2 inhibitor AZD2014 showed no considerable effects on embryonic cells of zebrafish in concentrations substantially toxic in cancer cells. AZD2014 also caused the least prominent effects on sea urchin embryo development compared to other inhibitors. Significant toxicity of AZD2014 in human cancer cells, its capacity to sensitize resistant cancers, lower antiproliferative activity against human normal cell lines and fast proliferating embryonic cells could make this agent a promising candidate for anticancer therapy.
Napomena:
This is a post-peer-review, pre-copyedit version of an article published in Acta Biologica Hungarica. The final authenticated version is available online at: https://dx.doi.org/10.1556/018.69.2018.4.3.
Related to: https://radar.ibiss.bg.ac.rs/handle/123456789/3231.
Ključne reči:
AZD2014; PI3K-Akt-mTOR signaling pathway; RAS-MAPK-ERK signaling pathway; zebrafish (Danio rerio); sea urchin (Arbacia lixula)Izvor:
Acta Biologica Hungarica, 2018, 69, 4, 395-410Finansiranje / projekti:
- Identifikacija molekularnih markera za predikciju progresije tumora, odgovora na terapiju i ishoda bolesti (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41031)
- Kompleksne bolesti kao model sistem za proučavanje modulacije fenotipa-strukturna i funkcionalna analiza molekularnih biomarkera (RS-MESTD-Basic Research (BR or ON)-173008)
DOI: 10.1556/018.69.2018.4.3
ISSN: 0236-5383
PubMed: 30587022
WoS: 000454455400003
Scopus: 2-s2.0-85059130260
URI
https://akjournals.com/view/journals/018/69/4/article-p395.xmlhttps://radar.ibiss.bg.ac.rs/123456789/3881