Details
| Originalsprache | Englisch |
|---|---|
| Seiten (von - bis) | 10-19 |
| Seitenumfang | 10 |
| Fachzeitschrift | Toxicology in vitro |
| Jahrgang | 53 |
| Publikationsstatus | Veröffentlicht - 23 Juli 2018 |
Abstract
The administration of immunosuppressive drugs is a necessary therapeutic measure in organ transplantation to prevent rejections. However, the use of temporarily high dosed immunosuppressive drugs is associated with cytotoxicity and adverse side effects that could induce endothelial dysfunction. The aim of this work is to evaluate the effect of the administrated drugs tacrolimus and mycophenolic acid (MPA) on human umbilical vein endothelial cells (HUVECs). Whereas MPA showed no significant toxicity in a dose-dependent manner, a dose-response curve of tacrolimus treatment could be obtained in 2D monolayer. Due to limited cell-cell and cell-extracellular matrix (ECM) interactions in 2D monolayers, 3D spheroids have been established. The comparison of IC50 values demonstrated that tacrolimus is more toxic towards endothelial cells in 3D spheroids (IC50 value = 27.19 μg/ml) than in 2D monolayers (IC50 value = 40.23 μg/ml). Moreover, the maximal trough level of tacrolimus achieved in immunosuppressive therapy (18 ng/ml) resulted in low disaggregation of the spheroids and decreased vessel areas with increased number of end points of tubular-like structures in the angiogenesis assay even if no toxic effect could be detected. Thus, our approach unseals very sensitive cytotoxic effects of tacrolimus on the vasculature in organ recipients after immunosuppressive therapy.
ASJC Scopus Sachgebiete
- Pharmakologie, Toxikologie und Pharmazie (insg.)
- Toxikologie
Zitieren
- Standard
- Harvard
- Apa
- Vancouver
- BibTex
- RIS
in: Toxicology in vitro, Jahrgang 53, 23.07.2018, S. 10-19.
Publikation: Beitrag in Fachzeitschrift › Artikel › Forschung › Peer-Review
}
TY - JOUR
T1 - Tacrolimus inhibits angiogenesis and induces disaggregation of endothelial cells in spheroids – Toxicity testing in a 3D cell culture approach
AU - Thoms, Stefanie
AU - Ali, Alaa Ibrahim
AU - Jonczyk, Rebecca
AU - Scheper, Thomas
AU - Blume, Cornelia
N1 - Funding information: This work has been carried out as an integral part of the BIOFABRICATION FOR NIFE initiative ZN3228/ZN3267 , which is financially supported by the Ministry of Lower Saxony and the VolkswagenStiftung .
PY - 2018/7/23
Y1 - 2018/7/23
N2 - The administration of immunosuppressive drugs is a necessary therapeutic measure in organ transplantation to prevent rejections. However, the use of temporarily high dosed immunosuppressive drugs is associated with cytotoxicity and adverse side effects that could induce endothelial dysfunction. The aim of this work is to evaluate the effect of the administrated drugs tacrolimus and mycophenolic acid (MPA) on human umbilical vein endothelial cells (HUVECs). Whereas MPA showed no significant toxicity in a dose-dependent manner, a dose-response curve of tacrolimus treatment could be obtained in 2D monolayer. Due to limited cell-cell and cell-extracellular matrix (ECM) interactions in 2D monolayers, 3D spheroids have been established. The comparison of IC50 values demonstrated that tacrolimus is more toxic towards endothelial cells in 3D spheroids (IC50 value = 27.19 μg/ml) than in 2D monolayers (IC50 value = 40.23 μg/ml). Moreover, the maximal trough level of tacrolimus achieved in immunosuppressive therapy (18 ng/ml) resulted in low disaggregation of the spheroids and decreased vessel areas with increased number of end points of tubular-like structures in the angiogenesis assay even if no toxic effect could be detected. Thus, our approach unseals very sensitive cytotoxic effects of tacrolimus on the vasculature in organ recipients after immunosuppressive therapy.
AB - The administration of immunosuppressive drugs is a necessary therapeutic measure in organ transplantation to prevent rejections. However, the use of temporarily high dosed immunosuppressive drugs is associated with cytotoxicity and adverse side effects that could induce endothelial dysfunction. The aim of this work is to evaluate the effect of the administrated drugs tacrolimus and mycophenolic acid (MPA) on human umbilical vein endothelial cells (HUVECs). Whereas MPA showed no significant toxicity in a dose-dependent manner, a dose-response curve of tacrolimus treatment could be obtained in 2D monolayer. Due to limited cell-cell and cell-extracellular matrix (ECM) interactions in 2D monolayers, 3D spheroids have been established. The comparison of IC50 values demonstrated that tacrolimus is more toxic towards endothelial cells in 3D spheroids (IC50 value = 27.19 μg/ml) than in 2D monolayers (IC50 value = 40.23 μg/ml). Moreover, the maximal trough level of tacrolimus achieved in immunosuppressive therapy (18 ng/ml) resulted in low disaggregation of the spheroids and decreased vessel areas with increased number of end points of tubular-like structures in the angiogenesis assay even if no toxic effect could be detected. Thus, our approach unseals very sensitive cytotoxic effects of tacrolimus on the vasculature in organ recipients after immunosuppressive therapy.
KW - 3D
KW - Angiogenesis
KW - Endothelial cells
KW - Spheroids
KW - Tacrolimus
KW - Toxicity
UR - http://www.scopus.com/inward/record.url?scp=85050520355&partnerID=8YFLogxK
U2 - 10.1016/j.tiv.2018.07.017
DO - 10.1016/j.tiv.2018.07.017
M3 - Article
C2 - 30048735
AN - SCOPUS:85050520355
VL - 53
SP - 10
EP - 19
JO - Toxicology in vitro
JF - Toxicology in vitro
SN - 0887-2333
ER -