Dynamics of Erythropoietic Biomarkers in Response to Treatment With Erythropoietin in Belgrade Rats

Nguyen, Ly M.; Singh, Anumeha; Wiczling, Paweł; Krzyzanski, Wojciech

doi:10.3389/fphar.2018.00316

Cited by 6 publications

(5 citation statements)

References 24 publications

(29 reference statements)

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“…The selection of response biomarker is very important for a bioassay. The biomarkers approach has been widely used for pharmacokinetic studies of high molecular weight compounds in vivo and in volunteers [33,34,35,36].…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Study of Bioactive Glycopeptide from Strongylocentrotus droebachiensis After Intranasal Administration to Rats Using Biomarker Approach

Shikov

Pozharitskaya²,

Фаустова³

et al. 2019

Marine Drugs

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A glycopeptide fraction (GPF) from internal organs of green sea urchins (Strongylocentrotus droebachiensis Müller, Strongylocentrotidae) has been reported to be an effective bronchitis treatment. In this study, we evaluated the pharmacokinetic and tissue distribution of GPF, following single and repeated intranasal (i/n) administration over the course of seven days in rats. The method measuring lactate dehydrogenase as biomarker was used to analyse the plasma and tissue concentrations of GPF. GPF appears in the plasma 15 min after single i/n administration (100 µg/kg) and reaches its maximum at 45 min. The area under the curve (AUC)0–24 and Cmax were similar using both i/n and intravenous administration, while mean residence time (MRT) and T1/2 after i/n administration were significantly higher compared with intravenous (i/v) administration. The absolute bioavailability of GPF after i/n administration was 89%. The values of tissue availability (ft) provided evidence about the highest concentration of GPF in the nose mucosa (ft = 34.9), followed by spleen (ft = 4.1), adrenal glands (ft = 3.8), striated muscle (ft = 1.8), kidneys (ft = 0.5), and liver (ft = 0.3). After repeated dose administration, GPF exhibited significantly higher AUC0–24 and MRT, indicating its accumulation in the plasma.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetic Study of Bioactive Glycopeptide from Strongylocentrotus droebachiensis After Intranasal Administration to Rats Using Biomarker Approach

Shikov

Pozharitskaya²,

Фаустова³

et al. 2019

Marine Drugs

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“…PK and PD Studies. The doses were selected based on approximately equivalent doses in humans (Krzyzanski et al, 2013;Nguyen et al, 2018). The study design was based on previous experiments (Ait-Oudhia et al, 2010b;Krzyzanski et al, 2013;Yan et al, 2013), as shown in Supplemental Fig.…”

Section: Methodsmentioning

confidence: 99%

Fate Determination Role of Erythropoietin and Romiplostim in the Lineage Commitment of Hematopoietic Progenitors

Fan

Krzyzanski

Wong

et al. 2022

J Pharmacol Exp Ther

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Erythropoietin (EPO) and thrombopoietin (TPO) have long been known to promote erythropoiesis and megakaryopoiesis, respectively. However, the fate-changing role of EPO and TPO on megakaryocyte-erythroid progenitors (MEPs) to develop along the erythroid versus megakaryocyte lineage remains unclear. We have previously shown that EPO may have a fate-changing role because EPO treatment could induce progenitor cells depletion and result in EPO resistance. Therefore, we hypothesize that a combination of romiplostim, a TPO receptor agonist that could stimulate the expansion of progenitors, with EPO can treat EPO resistance. Using rats with anemia due to chronic kidney disease, we demonstrated that romiplostim synergized with EPO to promote red blood cells production whereas EPO inhibited platelet production in a dose-dependent manner to reduce the risk of thrombosis. Corroborating findings from in vivo, in vitro experiments demonstrated that romiplostim expanded hematopoietic stem cells and stimulated megakaryopoiesis whereas EPO drove the progenitors toward an erythroid fate. We further developed a novel pharmacokinetic-pharmacodynamic model to quantify the effects of EPO and romiplostim on megakaryopoiesis and erythropoiesis simultaneously. The modeling results demonstrated that EPO increased the differentiation rate of MEPs into burst-forming unit-erythroid cells up to 22-fold, indicating that the slight increase of MEPs induced by romiplostim could be further amplified and recruited by EPO to promote erythropoiesis. The data herein support that romiplostim in combination with EPO can treat EPO resistance. SIGNIFICANCE STATEMENTThis study clarified that erythropoietin (EPO) drives the fate of megakaryocyte-erythroid progenitors (MEPs) toward the erythroid lineage, thus reducing their megakaryocyte (MK) lineage commitment, whereas romiplostim, a thrombopoietin receptor agonist, stimulates megakaryopoiesis through the MK-committed progenitor and MEP bifurcation pathways simultaneously. These findings support an innovative combination of romiplostim and EPO to treat EPO-resistant anemia because the combination therapy further promotes erythropoiesis compared to EPO monotherapy and inhibits platelet production compared to romiplostim monotherapy.

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“…Thus, the evidences point to the combination treatments causing apoptosis via a mechanism other than the caspase pathway. Since the activity of caspase-3 and-9 are promoted by the release of the caspase-activating cytochrome c from mitochondrial membrane depolarization, it is postulated that rHuEPO stabilized the mitochondrial membrane rHuEPO ( Nguyen et al, 2018 ), preventing the release of cytochrome c and up-regulation of caspases and activation of the caspase-dependent apoptotic pathway by tamoxifen. One of our earlier studies showed that 3D MCF-7 spheroids treatment with EPO alone reduced cell viability without caspases activation.…”

Section: Discussionmentioning

confidence: 99%

Recombinant human Erythropoietin enhanced the cytotoxic effects of tamoxifen toward the spheroid MCF-7 breast cancer cells

Edin

Al-Haj

Abdullah

et al. 2021

Saudi Journal of Biological Sciences

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Erythropoietin (EPO) is widely used to treat anemia in patients undergoing chemotherapy for cancers. The main objective of this study was to investigate the effect of rHuEPO on the response of spheroid breast cancer, MCF-7, cells to tamoxifen treatment. The MCF-7 spheroids were treated with 10 mg/mL tamoxifen in combination with either 0, 10, 100 or 200 IU/mL rHuEPO for 24, 48 or 72 h. The viability of the MCF-7 cells was determined using the annexin-V, cell cycle, caspases activation and acridine orange/propidium iodide staining. rHuEPO-tamoxifen combination significantly (p greater than 0.05) increased the number of spheroid MCF-7 cells entering early apoptotic phase after 12 h and late apoptotic phase after 24 h of treatment; primarily the result of the antiproliferative effect tamoxifen. Tamoxifen alone significantly (p < 0.05) increased the caspase-3 and −9 activities in the spheroid MCF-7 cells by 200 to 550% of the control. Combination rHuEPO and tamoxifen produced much lesser effect on the caspase-8 activity. The rHuEPO in the combination treatment had concentration-dependently caused decrease in the caspase activities. rHuEPO-tamoxifen combination markedly increased MCF-7 cells entering the SubG0/G1 phase of the cell cycle by more than 500% of the control, while decreasing those entering the G2 + M and S phases by 50%. After 72 h, the combination treatment produced greater (p < 0.05) change in the SubG0/G1 phase than tamoxifen treatment alone. Morphologically, spheroid MCF-7 cells subjected to combination rHuEPO-tamoxifen treatment showed nuclear condensation and margination, cytoplasmic blebbing, necrosis, and early and late apoptosis. Thus, the study showed that rHuEPO-tamoxifen combination induced apoptosis in the spheroid MCF-7 cells. The apoptotic effect of the rHuEPO-tamoxifen combination treatment on the MCF-7 cells was greater than that produced by tamoxifen alone. The rHuEPO-tamoxifen treatment enhanced the caspase-independent apoptotic effects of tamoxifen on the spheroid MCF-7 cells.

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Dynamics of Erythropoietic Biomarkers in Response to Treatment With Erythropoietin in Belgrade Rats

Cited by 6 publications

References 24 publications

Pharmacokinetic Study of Bioactive Glycopeptide from Strongylocentrotus droebachiensis After Intranasal Administration to Rats Using Biomarker Approach

Pharmacokinetic Study of Bioactive Glycopeptide from Strongylocentrotus droebachiensis After Intranasal Administration to Rats Using Biomarker Approach

Fate Determination Role of Erythropoietin and Romiplostim in the Lineage Commitment of Hematopoietic Progenitors

Recombinant human Erythropoietin enhanced the cytotoxic effects of tamoxifen toward the spheroid MCF-7 breast cancer cells

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