دورية أكاديمية
أعرض في EDS

Effective Treatment of Metastatic Melanoma by Combining MAPK and PI3K Signaling Pathway Inhibitors.

التفاصيل البيبلوغرافية
العنوان: Effective Treatment of Metastatic Melanoma by Combining MAPK and PI3K Signaling Pathway Inhibitors.
المؤلفون: 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, Jonas Lies vei 65, 5021 Bergen, Norway., Parajuli H; Kristian Gerhard Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway., Hoang T; Kristian Gerhard Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway., Feng Z; Kristian Gerhard Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway.; Brain Science Research Institute, Shandong University, 44 Wenhuaxi Road, Jinan 250100, China., Stokke K; Kristian Gerhard Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway., Wang J; Kristian Gerhard Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway.; Brain Science Research Institute, Shandong University, 44 Wenhuaxi Road, Jinan 250100, China., Roy K; Kristian Gerhard Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway., 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., Knappskog S; Department of Oncology and Medical Physics, Haukeland University Hospital, Jonas Lies vei 65, 5021 Bergen, Norway.; Section of Oncology, Department of Clinical Science, University of Bergen, 5020 Bergen, Norway., 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.; NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, 84 Val Fleuri, 1526 Luxembourg, Luxembourg. 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.
المصدر: International journal of molecular sciences [Int J Mol Sci] 2019 Aug 29; Vol. 20 (17). Date of Electronic Publication: 2019 Aug 29.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Basel, Switzerland : MDPI, [2000-
مواضيع طبية MeSH: Antineoplastic Combined Chemotherapy Protocols/*pharmacology , Brain Neoplasms/*prevention & control , Melanoma/*drug therapy , Mitogen-Activated Protein Kinases/*metabolism , Phosphatidylinositol 3-Kinases/*metabolism , Protein Kinase Inhibitors/*pharmacology , Signal Transduction/*drug effects , Skin Neoplasms/*drug therapy, Aminopyridines/administration & dosage ; Animals ; Brain Neoplasms/metabolism ; Brain Neoplasms/secondary ; Cell Line, Tumor ; Melanoma/metabolism ; Melanoma/pathology ; Mice, Inbred NOD ; Mice, SCID ; Morpholines/administration & dosage ; Pyridones/administration & dosage ; Pyrimidinones/administration & dosage ; Skin Neoplasms/metabolism ; Skin Neoplasms/pathology ; Treatment Outcome ; Tumor Burden/drug effects ; Xenograft Model Antitumor Assays
مستخلص: Malignant melanoma is the most aggressive type of skin cancer and is closely associated with the development of brain metastases. Despite aggressive treatment, the prognosis has traditionally been poor, necessitating improved therapies. In melanoma, the mitogen activated protein kinase and the phosphoinositide 3-kinase signaling pathways are commonly altered, and therapeutically inhibiting one of the pathways often upregulates the other, leading to resistance. Thus, combined treatment targeting both pathways is a promising strategy to overcome this. Here, we studied the in vitro and in vivo effects of the PI3K inhibitor buparlisib and the MEK1/2 inhibitor trametinib, used either as targeted monotherapies or in combination, on patient-derived melanoma brain metastasis cell lines. Scratch wound and trans-well assays were carried out to assess the migratory capacity of the cells upon drug treatment, whereas flow cytometry, apoptosis array and Western blots were used to study apoptosis. Finally, an in vivo treatment experiment was carried out on NOD/SCID mice. We show that combined therapy was more effective than monotherapy. Combined treatment also more effectively increased apoptosis, and inhibited tumor growth in vivo. This suggests a clinical potential of combined treatment to overcome ceased treatment activity which is often seen after monotherapies, and strongly encourages the evaluation of the treatment strategy on melanoma patients with brain metastases.
Competing Interests: The authors declare no conflict of interest.
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معلومات مُعتمدة: 182716, 5745046 Kreftforeningen; 911990 Helse Vest; N/A KG Jebsen
فهرسة مساهمة: Keywords: BRAF; MAPK; PI3K; apoptosis; brain metastasis; combined treatment; melanoma
المشرفين على المادة: 0 (Aminopyridines)
0 (Morpholines)
0 (NVP-BKM120)
0 (Protein Kinase Inhibitors)
0 (Pyridones)
0 (Pyrimidinones)
33E86K87QN (trametinib)
EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
تواريخ الأحداث: Date Created: 20190901 Date Completed: 20200203 Latest Revision: 20240720
رمز التحديث: 20240720
مُعرف محوري في PubMed: PMC6747502
DOI: 10.3390/ijms20174235
PMID: 31470659
قاعدة البيانات: MEDLINE
الوصف
تدمد:1422-0067
DOI:10.3390/ijms20174235