Bioeffects of Ultrasound-Stimulated Microbubbles on Endothelial Cells: Gene Expression Changes Associated with Radiation Enhancement In Vitro

Al‐Mahrouki, Azza; Karshafian, Raffi; Giles, Anoja; Czarnota, Gregory J.

doi:10.1016/j.ultrasmedbio.2012.07.009

Cited by 57 publications

(93 citation statements)

References 60 publications

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“…Following these mechanical changes, a range of biological effects on surrounding cells can be induced at physiological and tissue levels due to released energy. These biological effects include gene expression changes, as well as cell death and vascular shutdown [5,33]. Consistently, slightly increased vascular shutdown and tumor cell death were observed after USMB treatment in this study.…”

Section: Discussionsupporting

confidence: 88%

Ultrasound-Stimulated Microbubbles Enhance Radiosensitization of Nasopharyngeal Carcinoma

Deng

Cai

Feng

et al. 2018

Cell Physiol Biochem

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Background/Aims: Recent studies indicate that therapies targeting the vasculature can significantly sensitize tumors to radiation. Ultrasound-stimulated microbubbles (USMBs) are regarded as a promising radiosensitizer. In this study, we investigated the effect of USMBs on the sensitivity of nasopharyngeal carcinoma (NPC) to radiation. Methods: Human NPC (CNE-2) cells and human umbilical vein endothelial cells (HUVECs) were exposed to radiation (0, 2, and 8 Gy) alone or in combination with USMBs. Cell viability and apoptosis were measured with the MTT assay and flow cytometry, respectively. The angiogenic activity of HUVECs was detected using matrigel tubule formation. The in vitro effects induced by these treatments were confirmed in vivo with xenograft models of CNE-2 cells in nude mice by examining vascular integrity using color Doppler flow imaging and cell survival using immunohistochemistry. Additionally, the in vivo and in vitro expressions of angiotensin II (ANG II) and its receptor (AT1R) were detected by immunohistochemistry and western blotting, respectively. With CNE-2 cells and HUVECs transfected with control, ANG II, or AT1R, perindopril (an inhibitor of angiotensin-converting enzyme) and candesartan (an inhibitor of AT1R) were used to verify the role of ANG II and AT1R in the radiosensitivity of tumor and endothelial cells by USMBs, by determining cell viability and apoptosis and angiogenic activity. Results: In the NPC xenografts, USMBs slightly reduced blood flow and CD34 expression, increased tumor cell death and ANG II and AT1R expression, and significantly enhanced the effects of radiation. With CNE-2 cells and HUVECs, the USMBs further enhanced the inhibition of tumor cell viability and endothelial tubule formation and further enhanced the increase in ANG II and AT1R due to radiation. Furthermore, perindopril and candesartan significantly enhanced the inhibitory effect of radiation and USMBs on tumor cell growth and angiogenesis in vitro. Conclusions: We have demonstrated for the first time that USMB exposure can significantly enhance the destructive effect on NPC of radiation, and this effect might be further increased by ANG II and AT1R inhibition. Our findings suggest that USMBs can be used as a promising sensitizer of radiotherapy to treat NPC, and the clinical effect might be increased by ANG II and AT1R inhibition.

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Section: Discussionsupporting

confidence: 88%

Ultrasound-Stimulated Microbubbles Enhance Radiosensitization of Nasopharyngeal Carcinoma

Deng

Cai

Feng

et al. 2018

Cell Physiol Biochem

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“…Immunohistochemical ceramide staining confirmed the increase of ceramide as early as 1 h after microbubble insonification with cells and combined treatments. Consequently, Al-Mahrouki et al [66] tied cell-membrane metabolism gene activation to microbubble-based mechanical perturbation of endothelial cells. Microarray and real time quantitative PCR analysis of gene expression revealed an upregulation of a number of genes that code for peptides that are involved in membrane damage and de novo ceramide-generation.…”

Section: • Mechanisms Behind Mechanical Perturbation Of Cell Membranesmentioning

confidence: 99%

Biomechanical Effects of Microbubbles: From Radiosensitization to Cell Death

Kaffas

Czarnota

2015

Future Oncol.

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Ultrasound-stimulated microbubbles have been demonstrated to mechanically perturb cell membranes, resulting in the activation of biological signaling pathways that significantly enhance the effects of radiation. The underlying mechanism involves augmented ceramide production following both microbubble stimulation and irradiation, leading to rapid and extensive endothelial apoptosis and tumor cell death as a result of vascular collapse. Endothelial cells are particularly sensitive to ceramide-induced cell death due to an enriched presence of sphingomyelinase in their membranes. In tumors, this consequent rapid vascular shutdown translates to an overall increase in tumor responses to radiation treatments. This review summarizes the groundwork behind endothelial-based radiation enhancement with ultrasound-stimulated microbubbles, and presents ongoing research on the use of microbubbles as therapeutic agents in cancer therapy.

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“…FANCM which is a DNA translocase and highly related to DNA replication regulates checkpoint signaling and replication fork progression [55], [56]. Other genes, such as COX6B1 is related to cell apoptosis [57] and ESRRA also have been reported associated with cervical cancer [58]. In addition, among 45 integration events, 13 events led to antisense transcription of the coding sequences, such as PRDX5 , EBAG9 and CD28, etc .…”

Section: Discussionmentioning

confidence: 99%

Multiple-Integrations of HPV16 Genome and Altered Transcription of Viral Oncogenes and Cellular Genes Are Associated with the Development of Cervical Cancer

Lin

et al. 2014

PLoS ONE

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The constitutive expression of the high-risk HPV E6 and E7 viral oncogenes is the major cause of cervical cancer. To comprehensively explore the composition of HPV16 early transcripts and their genomic annotation, cervical squamous epithelial tissues from 40 HPV16-infected patients were collected for analysis of papillomavirus oncogene transcripts (APOT). We observed different transcription patterns of HPV16 oncogenes in progression of cervical lesions to cervical cancer and identified one novel transcript. Multiple-integration events in the tissues of cervical carcinoma (CxCa) are significantly more often than those of low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL). Moreover, most cellular genes within or near these integration sites are cancer-associated genes. Taken together, this study suggests that the multiple-integrations of HPV genome during persistent viral infection, which thereby alters the expression patterns of viral oncogenes and integration-related cellular genes, play a crucial role in progression of cervical lesions to cervix cancer.

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Bioeffects of Ultrasound-Stimulated Microbubbles on Endothelial Cells: Gene Expression Changes Associated with Radiation Enhancement In Vitro

Cited by 57 publications

References 60 publications

Ultrasound-Stimulated Microbubbles Enhance Radiosensitization of Nasopharyngeal Carcinoma

Ultrasound-Stimulated Microbubbles Enhance Radiosensitization of Nasopharyngeal Carcinoma

Biomechanical Effects of Microbubbles: From Radiosensitization to Cell Death

Multiple-Integrations of HPV16 Genome and Altered Transcription of Viral Oncogenes and Cellular Genes Are Associated with the Development of Cervical Cancer

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