Inhibition of mitochondrial respiration prevents BRAF-mutant melanoma brain metastasis.

Autor: Sundstrøm T; Kristian Gerhard Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009, Bergen, Norway.; Department of Clinical Medicine, University of Bergen, Haukelandsveien 22, 5021, Bergen, Norway.; Department of Neurosurgery, Haukeland University Hospital, Haukelandsveien 22, 5021, Bergen, Norway., Prestegarden L; Kristian Gerhard Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009, Bergen, Norway.; Department of Clinical Medicine, University of Bergen, Haukelandsveien 22, 5021, Bergen, Norway.; Department of Dermatology, Haukeland University Hospital, Haukelandsveien 22, 5021, Bergen, Norway., Azuaje F; NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, 84 Val Fleuri, 1526, Luxembourg, Luxembourg.; Present address: Proteome and Genome Research Unit, Department of Oncology, Luxembourg Institute of Health, 1A-B, rue Thomas Edison, L-1445, Strassen, Luxembourg, Luxembourg., Aasen SN; Kristian Gerhard Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009, Bergen, Norway.; Department of Oncology and Medical Physics, Haukeland University Hospital, Haukelandsveien 22, 5021, Bergen, Norway., Røsland GV; Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009, Bergen, Norway., Varughese JK; Kristian Gerhard Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009, Bergen, Norway., Bahador M; Kristian Gerhard Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009, Bergen, Norway., Bernatz S; Edinger-Institute (Neurological Institute), Goethe-University Medical School, Heinrich-Hoffmann-Strasse 7, 60528, Frankfurt am Main, Germany., Braun Y; Edinger-Institute (Neurological Institute), Goethe-University Medical School, Heinrich-Hoffmann-Strasse 7, 60528, Frankfurt am Main, Germany., Harter PN; Edinger-Institute (Neurological Institute), Goethe-University Medical School, Heinrich-Hoffmann-Strasse 7, 60528, Frankfurt am Main, Germany., Skaftnesmo KO; Institute of Marine Research, Nordnesgaten 50, 5005, Bergen, Norway., Ingham ES; Department of Biomedical Engineering, University of California Davis, 451 East Health Sciences Drive, Davis, CA, 95616, USA., Mahakian LM; Department of Biomedical Engineering, University of California Davis, 451 East Health Sciences Drive, Davis, CA, 95616, USA., Tam S; Department of Biomedical Engineering, University of California Davis, 451 East Health Sciences Drive, Davis, CA, 95616, USA., Tepper CG; Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, 4645 Second Avenue, Sacramento, CA, 95817, USA., Petersen K; Computational Biology Unit, Department of Informatics, University of Bergen, Thormøhlensgate 55, 5008, Bergen, Norway., Ferrara KW; Department of Biomedical Engineering, University of California Davis, 451 East Health Sciences Drive, Davis, CA, 95616, USA., Tronstad KJ; Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009, Bergen, Norway., Lund-Johansen M; Department of Clinical Medicine, University of Bergen, Haukelandsveien 22, 5021, Bergen, Norway.; Department of Neurosurgery, Haukeland University Hospital, Haukelandsveien 22, 5021, Bergen, Norway., Beschorner R; Institute of Pathology and Neuropathology, Department of Neuropathology, University of Tuebingen, Tuebingen, Germany., Bjerkvig R; Kristian Gerhard Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009, Bergen, Norway.; NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, 84 Val Fleuri, 1526, Luxembourg, Luxembourg., Thorsen F; Kristian Gerhard Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009, Bergen, Norway. frits.thorsen@uib.no.; The Molecular Imaging Center, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009, Bergen, Norway. frits.thorsen@uib.no.
Jazyk: angličtina
Zdroj: Acta neuropathologica communications [Acta Neuropathol Commun] 2019 Apr 10; Vol. 7 (1), pp. 55. Date of Electronic Publication: 2019 Apr 10.
DOI: 10.1186/s40478-019-0712-8
Abstrakt: Melanoma patients carry a high risk of developing brain metastases, and improvements in survival are still measured in weeks or months. Durable disease control within the brain is impeded by poor drug penetration across the blood-brain barrier, as well as intrinsic and acquired drug resistance. Augmented mitochondrial respiration is a key resistance mechanism in BRAF-mutant melanomas but, as we show in this study, this dependence on mitochondrial respiration may also be exploited therapeutically. We first used high-throughput pharmacogenomic profiling to identify potentially repurposable compounds against BRAF-mutant melanoma brain metastases. One of the compounds identified was β-sitosterol, a well-tolerated and brain-penetrable phytosterol. Here we show that β-sitosterol attenuates melanoma cell growth in vitro and also inhibits brain metastasis formation in vivo. Functional analyses indicated that the therapeutic potential of β-sitosterol was linked to mitochondrial interference. Mechanistically, β-sitosterol effectively reduced mitochondrial respiratory capacity, mediated by an inhibition of mitochondrial complex I. The net result of this action was increased oxidative stress that led to apoptosis. This effect was only seen in tumor cells, and not in normal cells. Large-scale analyses of human melanoma brain metastases indicated a significant role of mitochondrial complex I compared to brain metastases from other cancers. Finally, we observed completely abrogated BRAF inhibitor resistance when vemurafenib was combined with either β-sitosterol or a functional knockdown of mitochondrial complex I. In conclusion, based on its favorable tolerability, excellent brain bioavailability, and capacity to inhibit mitochondrial respiration, β-sitosterol represents a promising adjuvant to BRAF inhibitor therapy in patients with, or at risk for, melanoma brain metastases.
Databáze: MEDLINE
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