Abstract
Endothelial cell death caused by novel microbubble-enhanced ultrasound cancer therapy leads to secondary tumour cell death. In order to characterize and optimize these treatments, the molecular mechanisms resulting from the interaction with endothelial cells were investigated here. Endothelial cells (HUVEC) were treated with ultrasound-stimulated microbubbles (US/MB), radiation (XRT), or a combination of US/MB+XRT. Effects on cells were evaluated at 0, 3, 6, and 24 hours after treatment. Experiments took place in the presence of modulators of sphingolipid-based signalling including ceramide, fumonisin B1, monensin, and sphingosine-1-phosphate. Experimental outcomes were evaluated using histology, TUNEL, clonogenic survival methods, immuno-fluorescence, electron microscopy, and endothelial cell blood-vessel-like tube forming assays. Fewer cells survived after treatment using US/MB+XRT compared to either the control or XRT. The functional ability to form tubes was only reduced in the US/ MB+XRT condition in the control, the ceramide, and the sphingosine-1-phosphate treated groups. The combined treatment had no effect on tube forming ability in either the fumonisin B1 or in the monensin exposed groups, since both interfere with ceramide production at different cellular sites. In summary, experimental results supported the role of ceramide signalling as a key element in cell death initiation with treatments using US/MB+XRT to target endothelial cells.
Highlights
Conventional cancer therapies include: immunotherapy, chemotherapy, surgery, radiation, hormonal therapy, or a combination of these treatments
Cells treated with ultrasound-stimulated microbubbles (US/MB) demonstrated nuclear pyknosis and membrane effects by 3 hours after treatment
Cells which were exposed to the combined treatment of ultrasound-stimulated microbubbles and radiation demonstrated different morphological results with more prominent formation of apoptotic bodies and positive TUNEL staining (Figure 1 and Figure 2)
Summary
Conventional cancer therapies include: immunotherapy, chemotherapy, surgery, radiation, hormonal therapy, or a combination of these treatments. Despite the availability of many treatment approaches to treat diverse cancer types, a definite cure has not yet been reached. This is mainly due to the complicated biology of cancer, where hurdles such as treatment resistance and redundant cell signalling pathways are among contributors to treatment resistance. Microbubbles have been used in a variety of cancer-treatment applications. Investigating the effect of cavitating microbubbles in concentrating energy and manipulating the cell membrane started more than a decade ago, and has improved the targeted delivery of drugs and genes, resulting in improved therapeutic applications [1]. Recent preclinical studies have investigated this phenomenon in cancer therapy and have demonstrated a high efficacy when treating colon cancer models [2]
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