Involvement of Ceramide Signalling in Radiation-Induced Tumour Vascular Effects and Vascular-Targeted Therapy

Abstract

Sphingolipids are well-recognized critical components in several biological processes. Ceramides constitute a class of sphingolipid metabolites that are involved in important signal transduction pathways that play key roles in determining the fate of cells to survive or die. Ceramide accumulated in cells causes apoptosis; however, ceramide metabolized to sphingosine promotes cell survival and angiogenesis. Studies suggest that vascular-targeted therapies increase endothelial cell ceramide resulting in apoptosis that leads to tumour cure. Specifically, ultrasound-stimulated microbubbles (USMB) used as vascular disrupting agents can perturb endothelial cells, eliciting acid sphingomyelinase (ASMase) activation accompanied by ceramide release. This phenomenon results in endothelial cell death and vascular collapse and is synergistic with other antitumour treatments such as radiation. In contrast, blocking the generation of ceramide using multiple approaches, including the conversion of ceramide to sphingosine-1-phosphate (S1P), abrogates this process. The ceramide-based cell survival “rheostat” between these opposing signalling metabolites is essential in the mechanotransductive vascular targeting following USMB treatment. In this review, we aim to summarize the past and latest findings on ceramide-based vascular-targeted strategies, including novel mechanotransductive methodologies.

Opaganib Protects against Radiation Toxicity: Implications for Homeland Security and Antitumor Radiotherapy

“…The ability of opaganib to protect normal tissue from radiation damage supports its use in combination with radiotherapy for cancer patients. The current in vitro studies demonstrate that opaganib increases the toxicity of radiation toward tumorigenic cells, and this is consistent with reports by others that increased levels of ceramide (as occur in opaganib-treated tumor cells) sensitizes tumor cells to killing by radiation (reviewed in [ 26 , 71 ]). Importantly, opaganib administration to non-transformed cells (IEC6) did not increase their radiation sensitivity.…”

“…Sphingolipids also regulate the sensitivities of tumor cells to anticancer drugs and IR (reviewed in [ 20 , 21 , 22 ]). For example, the ability of sphingosine to promote apoptosis in response to radiation treatment of prostate cancer cells was described by Nava et al [ 23 ], and the role of the ceramide: S1P balance in regulating radiation sensitivity has been widely substantiated [ 24 , 25 , 26 ]. Therefore, disruption of metabolism of ceramide to S1P is a new method to enhance radiation sensitivity in tumor cells, while concurrently suppressing pathologic inflammation in adjacent tissues.…”

Acid Sphingomyelinase Inhibitor, Imipramine, Reduces Hippocampal Neuronal Death after Traumatic Brain Injury

“…We focused on targeting ASMase, which is an enzyme that hydrolyzes ASM to ceramide. In general, ASMase repairs damage to injured neurons, and ceramide regulates cellular proliferation, differentiation, and apoptosis by activating cell damage cascades [ 49 , 50 ]. However, under pathologic conditions, ASMase and ceramide levels are abnormally increased and induce neuronal death.…”

Solid Tumor Treatment via Augmentation of Bioactive C6 Ceramide Levels with Thermally Ablative Focused Ultrasound

“…Thermal effects range from tissue hyperthermia to coagulative necrosis, whereas mechanical effects run the gamut from endothelial cell sonoporation to microvascular ablation. Interestingly, FUS and radiation may synergize as ultrasound-mediated microbubble (USMB) cavitation has been used for increasing cell death and decreasing tumor growth in combination with radiation therapy 7–11 . Importantly, USMB cavitation increases total ceramide signaling.…”

“…Interestingly, FUS and radiation may synergize as ultrasound-mediated microbubble (USMB) cavitation has been used for increasing cell death and decreasing tumor growth in combination with radiation therapy [7][8][9][10][11] . Importantly, USMB cavitation increases total ceramide signaling.…”