title: Sorafenib exerts anti-glioma activity in vitro and in vivo.
abstract: Despite conventional treatment strategies glioblastoma, the most common malignant primary brain tumor, has a bad prognosis with median survival times of 12-15 months. In this study, the efficacy of sorafenib (Nexavar, BAY43-9006), a multikinase inhibitor, on glioblastoma cells was evaluated both in vitro and in vivo. Treatment of established or patient-derived glioblastoma cells with low concentrations of sorafenib caused a dramatic dose dependent inhibition of proliferation (IC(50), 1.5 microM) and induction of apoptosis and autophagy. Sorafenib inhibited phosphorylation of signal transducer and activator of transcription 3 (Stat3) and expression of cyclins, D and E. In contrast, AKT was not modulated by sorafenib. Most important, systemic delivery of sorafenib was well tolerated, and significantly suppressed intracranial glioma growth via inhibition of cell proliferation, induction of apoptosis and autophagy, and reduction of angiogenesis. Furthermore, intracranial growth inhibition by sorafenib was accompanied by a significant reduction in ph-Stat3 (Tyr 705) levels. In summary, sorafenib has potent anti-glioma activity in vitro and in vivo.
authors.affiliation: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA. msiegelin@t-online.de
authors.forename: Markus D
authors.initials: MD
authors.lastname: Siegelin
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Raskett
authors.forename: Candace A
authors.initials: CA
authors.lastname: Gilbert
authors.forename: Alonzo H
authors.initials: AH
authors.lastname: Ross
authors.forename: Dario C
authors.initials: DC
authors.lastname: Altieri
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D011897:Random Allocation; D000077157:Sorafenib; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib
references.citation: Clin Cancer Res. 2008 Aug 15;14(16):5124-30
references.pmid: 18698030
references.citation: J Clin Oncol. 2009 Apr 10;27(11):1800-5
references.pmid: 19255312
references.citation: Oncogene. 2002 Dec 5;21(55):8404-13
references.pmid: 12466961
references.citation: Cancer Res. 2006 Dec 15;66(24):11851-8
references.pmid: 17178882
references.citation: Methods Enzymol. 2009;453:273-86
references.pmid: 19216911
references.citation: Eur J Cancer. 2009 Mar;45(4):677-84
references.pmid: 19121577
references.citation: J Natl Compr Canc Netw. 2009 Apr;7(4):397-403
references.pmid: 19406040
references.citation: Cancer Cell. 2005 May;7(5):457-68
references.pmid: 15894266
references.citation: Neurosurg Focus. 2006 Apr 15;20(4):E6
references.pmid: 16709037
references.citation: Cancer Res. 2004 Oct 1;64(19):7099-109
references.pmid: 15466206
references.citation: Mol Cancer Ther. 2006 Sep;5(9):2378-87
references.pmid: 16985072
references.citation: Oncogene. 2010 Feb 25;29(8):1190-202
references.pmid: 19935717
references.citation: J Clin Invest. 2009 Mar;119(3):454-64
references.pmid: 19229106
references.citation: Mol Cancer Ther. 2010 Jan;9(1):67-78
references.pmid: 20053772
references.citation: Mol Cancer Ther. 2008 Nov;7(11):3519-26
references.pmid: 19001435
references.citation: Mol Cancer Res. 2008 Jan;6(1):21-30
references.pmid: 18184972
references.citation: Neuro Oncol. 2010 Mar;12(3):233-42
references.pmid: 20167811
references.citation: Neurochem Int. 2009 Jun;54(7):458-63
references.pmid: 19428789
references.citation: Hepatology. 2009 Dec;50(6):1861-70
references.pmid: 19821497
references.citation: Mol Cancer. 2009 Dec 10;8:118
references.pmid: 20003259
references.citation: Clin Cancer Res. 2008 Aug 1;14(15):4694-704
references.pmid: 18676737
references.citation: Cancer Res. 2007 Oct 1;67(19):9490-500
references.pmid: 17909059
references.citation: J Clin Oncol. 2005 Apr 1;23(10):2411-22
references.pmid: 15800333
references.citation: J Clin Oncol. 2007 Jun 1;25(16):2295-305
references.pmid: 17538176
references.citation: Nature. 2008 Oct 23;455(7216):1061-8
references.pmid: 18772890
references.citation: Mol Cancer Ther. 2007 Jun;6(6):1785-92
references.pmid: 17575107