Hydroxyurea‐induced senescent peripheral blood mesenchymal stromal cells inhibit bystander cell proliferation of JAK2V617F‐positive human erythroleukemia cells

Bjelica, Sunčica; Diklić, Miloš; Đikić, Dragoslava; Kovačić, Marijana; Subotički, Tijana; Ajtić, Olivera Mitrović; Radojković, Milica; Čokić, Vladan P.; Santibanez, Juan F

doi:10.1111/febs.14927

Cited by 9 publications

(14 citation statements)

References 59 publications

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“…In addition, HU can be extremely toxic to preimplantation embryos because it impacts blastocyst formation and development, compromises folliculogenesis, and reduces ovulation [12]. HU inactivates ribonucleotide reductase and inhibits DNA synthesis in proliferating cells, and can increase apoptosis and induce cell cycle changes [11,13,14]. Accordingly, HU exposure induced apoptosis of fetal tissue cells, which resulted in abnormal tissue development in offspring [15].…”

Section: Introductionmentioning

confidence: 99%

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Hydroxyurea affects in vitro porcine oocyte maturation through increased apoptosis and oxidative stress

et al. 2021

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Hydroxyurea (HU) is an FDA-approved drug used to treat a variety of diseases, especially malignancies, but is harmful to fertility. We used porcine oocytes as an experimental model to study the effect of HU during oocyte maturation. Exposure of cumulus-oocyte complexes (COCs) to 20 µM (p < 0.01) and 50 µM (p < 0.001) HU reduced oocyte maturation. Exposure to 20 µM HU induced approximately 1.5-fold and 2-fold increases in Caspase-3 (p < 0.001) and P53 (p < 0.01) gene expression levels in cumulus cells, respectively, increased Caspase-3 (p < 0.01) and P53 (p < 0.001) protein expression levels in metaphase II (MII) oocytes and increased the percentage of apoptotic cumulus cells (p < 0.001). In addition, HU decreased the mitochondrial membrane potential (Δφm) (p < 0.01 and p < 0.001) and glutathione (GSH) levels (p < 0.01 and p < 0.001) of both cumulus cells and MII oocytes, while increasing their reactive oxygen species (ROS) levels (p < 0.001). Following parthenogenetic activation of embryos derived from MII oocytes, exposure to 20 µM HU significantly reduced total blastocyst cell numbers (p < 0.001) and increased apoptosis of blastocyst cells (p < 0.001). Moreover, HU exposure reduced the rate of development of 2-cell, 4 -8 cell, blastocyst, and hatching stages after parthenogenetic activation (p < 0.05). Our findings indicate that exposure to 20 µM HU caused significant oxidative stress and apoptosis of MII oocytes during maturation, which affected their developmental ability. These results provide valuable information for safety assessments of HU.

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Section: Introductionmentioning

confidence: 99%

“…Accordingly, HU exposure induced apoptosis of fetal tissue cells, which resulted in abnormal tissue development in offspring [15]. HU can increase the production of reactive oxygen species (ROS) [8,16]. The carbamoyl nitroso group is an intermediate of HU that can participate in electron transfer, ROS formation, and oxidative stress [17].…”

Section: Introductionmentioning

confidence: 99%

Hydroxyurea affects in vitro porcine oocyte maturation through increased apoptosis and oxidative stress

et al. 2021

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“…Moreover, senescence induction by HU increases ROS levels along with the downregulation of SOD2 [ 155 ]. Similarly, peripheral blood MSCs (PB-MSCs) are also targeted by this agent [ 180 ]. HU induces a senescence-like phenotype in PB-MSC as it provokes substantial cell morphology changes accompanied by SA- β -gal and p16 INK4A expression with a discrete effect on p21 Cip1 expression.…”

Section: Hydroxyurea and Cellular Senescencementioning

confidence: 99%

“…Furthermore, HU-induced senescent PB-MSCs significantly inhibit the proliferation of erythroleukemia cells by secreting TGF- β 1 and elevated ROS production. Thus, senescent PB-MSCs may shift from a tumor-promoter activity to a tumor-suppressive function [ 180 ].…”

Section: Hydroxyurea and Cellular Senescencementioning

confidence: 99%

Mechanisms of Hydroxyurea‐Induced Cellular Senescence: An Oxidative Stress Connection?

Kapor

Čokić

Santibáñez

2021

Oxidative Medicine and Cellular Longevity

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Hydroxyurea (HU) is a water-soluble antiproliferative agent used for decades in neoplastic and nonneoplastic conditions. HU is considered an essential medicine because of its cytoreduction functions. HU is an antimetabolite that inhibits ribonucleotide reductase, which causes a depletion of the deoxyribonucleotide pool and dramatically reduces cell proliferation. The proliferation arrest, depending on drug concentration and exposure, may promote a cellular senescence phenotype associated with cancer cell therapy resistance and inflammation, influencing neighboring cell functions, immunosuppression, and potential cancer relapse. HU can induce cellular senescence in both healthy and transformed cells in vitro, in part, because of increased reactive oxygen species (ROS). Here, we analyze the main molecular mechanisms involved in cytotoxic/genotoxic HU function, the potential to increase intracellular ROS levels, and the principal features of cellular senescence induction. Understanding the mechanisms involved in HU’s ability to induce cellular senescence may help to improve current chemotherapy strategies and control undesirable treatment effects in cancer patients and other diseases.

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“…We previously demonstrated that HU induces a senescence-like phenotype in peripheral blood MSCs, which reduces its capacity to support human erythroleukemia cell proliferation in vitro [30]. However, whether HU influences the inherent biological MSCs roles is not well elucidated so far.…”

Section: Introductionmentioning

confidence: 99%

Hydroxyurea Induces Bone Marrow Mesenchymal Stromal Cells Senescence and Modifies Cell Functionality In Vitro

Kapor

Vukotić

Subotički

et al. 2021

JPM

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Hydroxyurea (HU) is an antineoplastic agent that functions as an antimetabolite compound by inhibiting the ribonucleotide reductase. HU acts mainly as a cytostatic drug that through DNA replication stress may trigger a premature senescence-like cell phenotype, though its influence on bone marrow-derived mesenchymal stem/stromal cell (BMMSC) functions has not elucidated yet. Our results indicate that HU inhibits the growth of human BMMSC alongside senescence-like changes in both morphology and replicative potential, provokes cell cycle arrest at the S phase without affecting cellular viability and induces the expression of senescence-associated β-galactosidase and p16INK4. Moreover, HU-induced senescent BMMSC, although they did not change MSC markers expression, exhibited reduced capacity osteogenic and adipogenic differentiation. Conversely, HU treatment increased immunoregulatory functions of BMMSC compared with untreated cells and determined by T-cell proliferation. Interestingly, HU did not influence the capacity of BMMSC to induce monocytic myeloid-derived suppressor cells. Thus, these results suggest that HU improves the BMMSC functions on the T-cell inhibition and preserves their interaction with myeloid cell compartment. Mechanistically, BMMSC under HU treatment displayed a downregulation of mTOR and p38 MAPK signaling that may explain the reduced cell differentiation and increased immunomodulation activities. Together, the results obtained in this investigation suggest that HU by inducing senescence-like phenotype of BMMSC influences their cellular differentiation and immunoregulatory functions.

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Hydroxyurea‐induced senescent peripheral blood mesenchymal stromal cells inhibit bystander cell proliferation of JAK2V617F‐positive human erythroleukemia cells

Cited by 9 publications

References 59 publications

Hydroxyurea affects in vitro porcine oocyte maturation through increased apoptosis and oxidative stress

Hydroxyurea affects in vitro porcine oocyte maturation through increased apoptosis and oxidative stress

Mechanisms of Hydroxyurea‐Induced Cellular Senescence: An Oxidative Stress Connection?

Hydroxyurea Induces Bone Marrow Mesenchymal Stromal Cells Senescence and Modifies Cell Functionality In Vitro

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