Comparative toxicity evaluation of targeted anticancer therapeutics in embryonic zebrafish and sea urchin models
Само за регистроване кориснике
2018
Аутори
Babić, TamaraDinić, Jelena
Stojković Burić, Sonja
Hadzić, Stefan
Pesić, Milica
Radojković, Dragica
Divac Rankov, Aleksandra
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
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 mTO...RC1/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.
Кључне речи:
zebrafish (Danio rerio) / sea urchin (Arbacia lixula) / RAS-MAPK-ERK signaling pathway / PI3K-Akt-mTOR signaling pathway / AZD2014Извор:
Acta Biologica Hungarica, 2018, 69, 4, 395-410Издавач:
- Akademiai Kiado Zrt, Budapest
Финансирање / пројекти:
- Комплексне болести као модел систем за проучавање модулације фенотипа-структурна и функционална анализа молекуларних биомаркера (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
Институција/група
Institut za molekularnu genetiku i genetičko inženjerstvoTY - JOUR AU - Babić, Tamara AU - Dinić, Jelena AU - Stojković Burić, Sonja AU - Hadzić, Stefan AU - Pesić, Milica AU - Radojković, Dragica AU - Divac Rankov, Aleksandra PY - 2018 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/1132 AB - 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. PB - Akademiai Kiado Zrt, Budapest T2 - Acta Biologica Hungarica T1 - Comparative toxicity evaluation of targeted anticancer therapeutics in embryonic zebrafish and sea urchin models EP - 410 IS - 4 SP - 395 VL - 69 DO - 10.1556/018.69.2018.4.3 ER -
@article{ author = "Babić, Tamara and Dinić, Jelena and Stojković Burić, Sonja and Hadzić, Stefan and Pesić, Milica and Radojković, Dragica and Divac Rankov, Aleksandra", year = "2018", abstract = "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.", publisher = "Akademiai Kiado Zrt, Budapest", journal = "Acta Biologica Hungarica", title = "Comparative toxicity evaluation of targeted anticancer therapeutics in embryonic zebrafish and sea urchin models", pages = "410-395", number = "4", volume = "69", doi = "10.1556/018.69.2018.4.3" }
Babić, T., Dinić, J., Stojković Burić, S., Hadzić, S., Pesić, M., Radojković, D.,& Divac Rankov, A.. (2018). Comparative toxicity evaluation of targeted anticancer therapeutics in embryonic zebrafish and sea urchin models. in Acta Biologica Hungarica Akademiai Kiado Zrt, Budapest., 69(4), 395-410. https://doi.org/10.1556/018.69.2018.4.3
Babić T, Dinić J, Stojković Burić S, Hadzić S, Pesić M, Radojković D, Divac Rankov A. Comparative toxicity evaluation of targeted anticancer therapeutics in embryonic zebrafish and sea urchin models. in Acta Biologica Hungarica. 2018;69(4):395-410. doi:10.1556/018.69.2018.4.3 .
Babić, Tamara, Dinić, Jelena, Stojković Burić, Sonja, Hadzić, Stefan, Pesić, Milica, Radojković, Dragica, Divac Rankov, Aleksandra, "Comparative toxicity evaluation of targeted anticancer therapeutics in embryonic zebrafish and sea urchin models" in Acta Biologica Hungarica, 69, no. 4 (2018):395-410, https://doi.org/10.1556/018.69.2018.4.3 . .