Intracellular Signaling in Key Pathways Is Induced by Treatment with Ultrasound and Microbubbles in a Leukemia Cell Line, but Not in Healthy Peripheral Blood Mononuclear Cells

Autor:	Anika Langer, Bjørn Tore Gjertsen, Spiros Kotopoulis, Stein-Erik Gullaksen, Silje Maria Sundøy, Emmet McCormack, Ragnhild Haugse
Rok vydání:	2019
Předmět:	lcsh:RS1-441 Pharmaceutical Science Peripheral blood mononuclear cell Article microbubbles Flow cytometry lcsh:Pharmacy and materia medica 03 medical and health sciences 0302 clinical medicine cellular stress medicine sonoporation Viability assay Protein kinase B 030304 developmental biology 0303 health sciences medicine.diagnostic_test ultrasound phosphorylation Chemistry intracellular signaling ultrasound contrast agents Molecular biology 3. Good health 030220 oncology & carcinogenesis drug delivery Cancer cell Microbubbles Sonoporation Intracellular
Zdroj:	Pharmaceutics Volume 11 Issue 7 Pharmaceutics, Vol 11, Iss 7, p 319 (2019)
ISSN:	1999-4923
DOI:	10.3390/pharmaceutics11070319
Popis:	Treatment with ultrasound and microbubbles (sonoporation) to enhance therapeutic efficacy in cancer therapy is rapidly expanding, but there is still very little consensus as to why it works. Despite the original assumption that pore formation in the cell membrane is responsible for increased uptake of drugs, the molecular mechanisms behind this phenomenon are largely unknown. We treated cancer cells (MOLM-13) and healthy peripheral blood mononuclear cells (PBMCs) with ultrasound at three acoustic intensities (74, 501, 2079 mW/cm2) ± microbubbles. We subsequently monitored the intracellular response of a number of key signaling pathways using flow cytometry or western blotting 5 min, 30 min and 2 h post-treatment. This was complemented by studies on uptake of a cell impermeable dye (calcein) and investigations of cell viability (cell count, Hoechst staining and colony forming assay). Ultrasound + microbubbles resulted in both early changes (p38 (Arcsinh ratio at high ultrasound + microbubbles: +0.5), ERK1/2 (+0.7), CREB (+1.3), STAT3 (+0.7) and AKT (+0.5)) and late changes (ribosomal protein S6 (Arcsinh ratio at low ultrasound: +0.6) and eIF2&alpha in protein phosphorylation). Observed changes in protein phosphorylation corresponded to changes in sonoporation efficiency and in viability, predominantly in cancer cells. Sonoporation induced protein phosphorylation in healthy cells was pronounced (p38 (+0.03), ERK1/2 (&minus 0.03), CREB (+0.0), STAT3 (&minus 0.1) and AKT (+0.04) and S6 (+0.2)). This supports the hypothesis that sonoporation may enhance therapeutic efficacy of cancer treatment, without causing damage to healthy cells.
Databáze:	OpenAIRE
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