Nitric Oxide Synthase Dependency in Hydroxyurea Inhibition of Erythroid Progenitor Growth
Аутори
Subotički, TijanaMitrović-Ajtić, Olivera
Đikić, Dragoslava
Santibanez, Juan F.
Tošić, Milica
Čokić, Vladan
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
Hydroxyurea (HU) causes nitric oxide (NO) bioactivation, acting as both a NO donor and a stimulator of NO synthase (NOS). To examine whether HU effects are NO mediated by chemical degradation or enzymatic induction, we studied human and mouse erythroid cells during proliferation, apoptosis, and differentiation. The HU and NO donor demonstrated persisted versus temporary inhibition of erythroid cell growth during differentiation, as observed by γ-and β-globin gene expression. HU decreased the percentage of erythroleukemic K562 cells in the G2/M phase that was reversed by N-nitro l-arginine methyl ester hydrochloride (L-NAME). Besides activation of endothelial NOS, HU significantly increased apoptosis of K562 cells, again demonstrating NOS dependence. Administration of HU to mice significantly inhibited colony-forming unit-erythroid (CFU-E), mediated by NOS. Moreover, burst-forming-units-erythroid (BFU-E) and CFU-E ex vivo growth was inhibited by the administration of nitrate or nitrite ...to mice. Chronic in vivo NOS inhibition with L-NAME protected the bone marrow cellularity despite HU treatment of mice. NO metabolites and HU reduced the frequency of NOS-positive cells from CFU-E and BFU-E colonies that was reverted by NOS inhibition. HU regulation of the G2/M phase, apoptosis, differentiation, cellularity, and NOS immunoreactive cells was NOS dependent. Inhalation of NO therapy as well as strategies to increase endogenous NO production could replace or enhance HU activity.
Кључне речи:
apoptosis / cell cycle / erythroid progenitors / hydroxyurea / nitric oxide synthaseИзвор:
Genes, 2021, 12, 8, 1145-Издавач:
- Multidisciplinary Digital Publishing Institute (MDPI)
Финансирање / пројекти:
- HUMANE - Hydroxyurea-Mediated Activation of Nitric Oxide Synthase in Erythroid Progenitors (RS-ScienceFundRS-Promis-6061921)
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200015 (Универзитет у Београду, Институт за медицинска истраживања) (RS-MESTD-inst-2020-200015)
Институција/група
Institut za medicinska istraživanjaTY - JOUR AU - Subotički, Tijana AU - Mitrović-Ajtić, Olivera AU - Đikić, Dragoslava AU - Santibanez, Juan F. AU - Tošić, Milica AU - Čokić, Vladan PY - 2021 UR - http://rimi.imi.bg.ac.rs/handle/123456789/1151 AB - Hydroxyurea (HU) causes nitric oxide (NO) bioactivation, acting as both a NO donor and a stimulator of NO synthase (NOS). To examine whether HU effects are NO mediated by chemical degradation or enzymatic induction, we studied human and mouse erythroid cells during proliferation, apoptosis, and differentiation. The HU and NO donor demonstrated persisted versus temporary inhibition of erythroid cell growth during differentiation, as observed by γ-and β-globin gene expression. HU decreased the percentage of erythroleukemic K562 cells in the G2/M phase that was reversed by N-nitro l-arginine methyl ester hydrochloride (L-NAME). Besides activation of endothelial NOS, HU significantly increased apoptosis of K562 cells, again demonstrating NOS dependence. Administration of HU to mice significantly inhibited colony-forming unit-erythroid (CFU-E), mediated by NOS. Moreover, burst-forming-units-erythroid (BFU-E) and CFU-E ex vivo growth was inhibited by the administration of nitrate or nitrite to mice. Chronic in vivo NOS inhibition with L-NAME protected the bone marrow cellularity despite HU treatment of mice. NO metabolites and HU reduced the frequency of NOS-positive cells from CFU-E and BFU-E colonies that was reverted by NOS inhibition. HU regulation of the G2/M phase, apoptosis, differentiation, cellularity, and NOS immunoreactive cells was NOS dependent. Inhalation of NO therapy as well as strategies to increase endogenous NO production could replace or enhance HU activity. PB - Multidisciplinary Digital Publishing Institute (MDPI) T2 - Genes T1 - Nitric Oxide Synthase Dependency in Hydroxyurea Inhibition of Erythroid Progenitor Growth IS - 8 SP - 1145 VL - 12 DO - 10.3390/genes12081145 ER -
@article{ author = "Subotički, Tijana and Mitrović-Ajtić, Olivera and Đikić, Dragoslava and Santibanez, Juan F. and Tošić, Milica and Čokić, Vladan", year = "2021", abstract = "Hydroxyurea (HU) causes nitric oxide (NO) bioactivation, acting as both a NO donor and a stimulator of NO synthase (NOS). To examine whether HU effects are NO mediated by chemical degradation or enzymatic induction, we studied human and mouse erythroid cells during proliferation, apoptosis, and differentiation. The HU and NO donor demonstrated persisted versus temporary inhibition of erythroid cell growth during differentiation, as observed by γ-and β-globin gene expression. HU decreased the percentage of erythroleukemic K562 cells in the G2/M phase that was reversed by N-nitro l-arginine methyl ester hydrochloride (L-NAME). Besides activation of endothelial NOS, HU significantly increased apoptosis of K562 cells, again demonstrating NOS dependence. Administration of HU to mice significantly inhibited colony-forming unit-erythroid (CFU-E), mediated by NOS. Moreover, burst-forming-units-erythroid (BFU-E) and CFU-E ex vivo growth was inhibited by the administration of nitrate or nitrite to mice. Chronic in vivo NOS inhibition with L-NAME protected the bone marrow cellularity despite HU treatment of mice. NO metabolites and HU reduced the frequency of NOS-positive cells from CFU-E and BFU-E colonies that was reverted by NOS inhibition. HU regulation of the G2/M phase, apoptosis, differentiation, cellularity, and NOS immunoreactive cells was NOS dependent. Inhalation of NO therapy as well as strategies to increase endogenous NO production could replace or enhance HU activity.", publisher = "Multidisciplinary Digital Publishing Institute (MDPI)", journal = "Genes", title = "Nitric Oxide Synthase Dependency in Hydroxyurea Inhibition of Erythroid Progenitor Growth", number = "8", pages = "1145", volume = "12", doi = "10.3390/genes12081145" }
Subotički, T., Mitrović-Ajtić, O., Đikić, D., Santibanez, J. F., Tošić, M.,& Čokić, V.. (2021). Nitric Oxide Synthase Dependency in Hydroxyurea Inhibition of Erythroid Progenitor Growth. in Genes Multidisciplinary Digital Publishing Institute (MDPI)., 12(8), 1145. https://doi.org/10.3390/genes12081145
Subotički T, Mitrović-Ajtić O, Đikić D, Santibanez JF, Tošić M, Čokić V. Nitric Oxide Synthase Dependency in Hydroxyurea Inhibition of Erythroid Progenitor Growth. in Genes. 2021;12(8):1145. doi:10.3390/genes12081145 .
Subotički, Tijana, Mitrović-Ajtić, Olivera , Đikić, Dragoslava, Santibanez, Juan F., Tošić, Milica, Čokić, Vladan, "Nitric Oxide Synthase Dependency in Hydroxyurea Inhibition of Erythroid Progenitor Growth" in Genes, 12, no. 8 (2021):1145, https://doi.org/10.3390/genes12081145 . .