Abstract P5-06-07: Artemisinin Disrupts the Barrier Function in Vascular Endothelial Cells, a Potential Implication in Improving Penetration of Therapeutic Drugs in the Central Nervous System
Authors: Jiang WG , Mason MD , Mansel RE. 
Published: April 2011

Introduction. The barrier functions of endothelial cells are primarily controlled by tight junctions in the vascular lining. Tight junctions are also the main cellular structure that makes up the Blood Brain Barrier (BBB) in the central nervous system (CNS). Treating brain tumours, primary and secondary, has been a difficult issue, one of the key reasons being drug permeability in the CNS by BBB. It has been shown recently that that in metastatic brain tumours, the Blood Brain Barriers remain intact. Thus, this presents a significant challenge for delivering sufficient anticancer agents in the CNS. Artemisinin is an anti-malarial drug that has been widely used. It is an effective modality in treating the cerebral type of malaria due to its ability to pass the BBB. The drug has been shown in recent years to be toxic to a variety of cancer cells and has been attempted in the treatment of certain solid tumours.

Aims. To investigate if Artemisinin a direct effect on the tight junctions in vascular endothelial cells.

Materials and methods. An established human vascular endothelial cell line was used. The effect of Artemisinin on the barrier function, migration and micromotion of the endothelial cells was investigated using an automatic barrier function assay, Electric cell-substrate impedance sensing (ECIS). Cells were treated with a broad range of concentrations over various periods. Barrier function, cell migration and cell micromotion functions were monitored and analysed using an automated cell analysis software. The effect of Artemisinin on the toxicity of the endothelial cells was also monitored.

Results. Artemisinin had a marginal toxic effect on endothelial cells at concentrations over 500μM. Subsequent tests were conducted at concentrations below toxic level. Low concentrations of Artemisinin (0.5-10 μM) resulted in a significant reduction of the barrier function in the endothelial cells (for example, barrier function measured by electric resistance in non-treated cells being 75.3±3.4Ω compared with 48.9±2.2Ω when cell treated with Artemisinin at 4μM). Using an electric wounding assay, we failed to detect a significant change in cell motility when cells were treated with Artemisinin. However, it is interesting to note that Artemisinin consistently increased the cell membrane micromotion over a wide concentrations between 0.1-100 μM. For example, cell modelling analysis showed that micromotion Rb in non-treated cells was 5.8±1.2Ω compared with 9.7±4.3Ω of cells treated with Artemisinin. Our data further demonstrated that the effect of Artemisinin on the barrier function of the cells sustained over a period of 4 hours.

Conclusion. Artemisinin is able to disrupt the barrier function of vascular endothelial cells without exerting significant cytotoxicity to the cells. The compound has a potential in being considered as a way to improve the permeability of endothelial cells during the delivery of anticancer drugs in the treatment of CNS malignancies.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-06-07.