Microbubble-based enhancement of radiation effect: Role of cell membrane ceramide metabolism

Abstract

Ultrasound (US) stimulated microbubbles (MB) is a new treatment approach that sensitizes cancer cells to radiation (XRT). The molecular pathways in this response remain unelucidated, however, previous data has supported a role for cell membrane-metabolism related pathways including an up regulation of UDP glycosyltransferase 8 (UGT8), which catalyzes the transfer of galactose to ceramide, a lipid that is associated with the induction of apoptotic signalling. In this study, the role of UGT8 in responses of prostate tumours to ultrasound-stimulated microbubble radiation enhancement therapy is investigated. Experiments were carried out with cells in vitro and tumours in vivo in which UGT8 levels had been up regulated or down regulated. Genetically modified PC3 cells were treated with XRT, US+MB, or a combination of XRT+US+MB. An increase in the immunolabelling of ceramide was observed in cells where UGT8 was down-regulated as opposed to cells where UGT8 was either not regulated or was up-regulated. Clonogenic assays have revealed a decreased level of cellular survival with the down-regulation of UGT8. Xenograft tumours generated from stably transfected PC3 cells were also treated with US+MB, XRT or US+MB+XRT. Histology demonstrated more cellular damage in tumours with down-regulated UGT8 in comparison with control tumours. In contrast, tumours with up-regulated UGT8 had less damage than control tumours. Power Doppler imaging indicated a reduction in the vascular index with UGT8 down-regulation and photoacoustic imaging revealed a reduction in oxygen saturation. This was contrary to when UGT8 was up regulated. The down regulation of UGT8 led to the accumulation of ceramide resulting in more cell death signalling and therefore, a greater enhancement of radiation effect when vascular disruption takes place through the use of ultrasound-stimulated microbubbles.

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

“…Results revealed that UGT8 down-regulated cells accumulated ceramide, demonstrating a significant reduction in cell survival as compared to control and up-regulated groups. The study further evaluated tumour response in vivo using PC3 tumours xenograft in which UGT8 was up and down-regulated [ 88 ] (this is explained in detail in the section below).…”

Focused ultrasound: tumour ablation and its potential to enhance immunological therapy to cancer

“…33,34 Some studies showed that when acoustic cavitation is combined with radiation or chemotherapy, enhanced therapeutic effects are observed. 35 For example, when treating in vivo 45 cases of bladder cancer in mice, Tran et al 36 showed additive antitumour and antivascular effects when ultrasound microbubbles were combined with radiation, thus opening up a wide spectrum of possibilities for future treatment of human cancer. Moreover, cavitation mechanism can indirectly cause the formation of a lithotripsy shockwaves that seems to present broad potential for non-thermal biologic effect in treating tumour, even if limited experiences reports that lithotripsy associated with cavitation phaenomenon may increase the development of distance metastasis.…”

Ultrasound-guided Microbubble in the Treatment of Cancer: A Mini Narrative Review

“…One remarkable study explored the effect of low-frequency low-intensity ultrasound with microbubble on the hypoxia environment of prostate cancer [ 10 ]. Another noteworthy study analyzed the role of UDP glycosyltransferase 8 (UGT8) in the responses of prostate tumor to ultrasound-stimulated microbubble radiation enhancement therapy [ 11 ].…”