211 Basic fibroblast growth factor inhibits radiation-induced apoptosis of endothelial cells by inhibiting acid sphingomyelinase activity

Biomechanical Effects of Microbubbles: From Radiosensitization to Cell Death

“…The effects of lower and more commonly clinically utilized 2 Gy radiation doses on the membrane of endothelial cells are thought to be minimal in comparison to doses greater than 8-10 Gy, resulting in functionally no biologically active production of ceramide ( Figure 3) [55]. Pretreating endothelial cells with bFGF or sphingosine-1-phosphate (S1P), the latter known to prevent the upregulation of ASMase, counters ceramide-induced endothelial cell apoptosis [58]. One proposed reason why endothelial cells may respond differently to radiation in comparison to other cell types is due to a membrane-based approximate 20-fold enrichment of a nonlysosomal secretory form of the ASMase enzyme [59].…”

“…S1P: Sphingosine-1-phosphate. Mechanical forces exerted on endothelial cell membranes can control a cells fate to promote survival or death [58][59][60][61][62][63]. Tumor endothelial cells, in particular, characteristically differ from normal tissue endothelial cells and tend to be more sensitive to such stress [62].…”

Dose-dependent response of tumor vasculature to radiation therapy in combination with Sunitinib depicted by three-dimensional high-frequency power Doppler ultrasound

“…Rapid endothelial apoptosis due to high radiation doses has been linked to a 20-fold enrichment of the ASMase enzyme in endothelial membranes compared to epithelial and tumor cells. High doses of radiotherapy ( [8][9][10] are suggested to cause substantial damage to the endothelial cell's membrane, leading to extensive hydrolyzation by the ASMase enzyme, in turn releasing ceramide to signal for apoptosis. At high radiation doses, endothelial cells can undergo apoptosis through two pathways: by DNA damage, or via a ceramide-signalling apoptosis pathway [3,[10][11][12][13][14][15].…”

“…Conventional radiation doses are believed not to activate the ceramide-dependent apoptosis pathway. Basic fibroblast growth factor (bFGF) has been shown to inhibit ceramide-dependent messaging for apoptosis [10,[15][16][17][18][19]. In comparison, epithelial and tumor cells are predominantly damaged through direct or indirect DNA damage, and undergo cell death or senescence only when they have accumulated adequate damage [9,20,21].…”

“…Basic fibroblast growth factor is a polypeptide produced by several cells, fibroblasts and endothelial cells and is one of the putative factors inducing angiogenic and stromal response in hosts. It is involved in mitogenesis, angiogenesis, cellular differentiation and tissue repair, and has been demonstrated to protect endothelial cells from lethal effects after exposure to clinically relevant radiation doses [10,15,16,18,19]. Our rational in using bFGF as an endothelial radio-protector is to reduce rapid endothelial cell death, which occurs predominantly via a ceramide signalling pathway after high-radiation doses.…”