Sorafenib exerts anti-glioma activity in vitro and in vivo.
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.
Siegelin
Markus D
MD
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA. msiegelin@t-online.de
Raskett
Christopher M
CM
Gilbert
Candace A
CA
Ross
Alonzo H
AH
Altieri
Dario C
DC
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
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib
Clin Cancer Res. 2008 Aug 15;14(16):5124-30
18698030
J Clin Oncol. 2009 Apr 10;27(11):1800-5
19255312
Oncogene. 2002 Dec 5;21(55):8404-13
12466961
Cancer Res. 2006 Dec 15;66(24):11851-8
17178882
Methods Enzymol. 2009;453:273-86
19216911
Eur J Cancer. 2009 Mar;45(4):677-84
19121577
J Natl Compr Canc Netw. 2009 Apr;7(4):397-403
19406040
Cancer Cell. 2005 May;7(5):457-68
15894266
Neurosurg Focus. 2006 Apr 15;20(4):E6
16709037
Cancer Res. 2004 Oct 1;64(19):7099-109
15466206
Mol Cancer Ther. 2006 Sep;5(9):2378-87
16985072
Oncogene. 2010 Feb 25;29(8):1190-202
19935717
J Clin Invest. 2009 Mar;119(3):454-64
19229106
Mol Cancer Ther. 2010 Jan;9(1):67-78
20053772
Mol Cancer Ther. 2008 Nov;7(11):3519-26
19001435
Mol Cancer Res. 2008 Jan;6(1):21-30
18184972
Neuro Oncol. 2010 Mar;12(3):233-42
20167811
Neurochem Int. 2009 Jun;54(7):458-63
19428789
Hepatology. 2009 Dec;50(6):1861-70
19821497
Mol Cancer. 2009 Dec 10;8:118
20003259
Clin Cancer Res. 2008 Aug 1;14(15):4694-704
18676737
Cancer Res. 2007 Oct 1;67(19):9490-500
17909059
J Clin Oncol. 2005 Apr 1;23(10):2411-22
15800333
J Clin Oncol. 2007 Jun 1;25(16):2295-305
17538176
Nature. 2008 Oct 23;455(7216):1061-8
18772890
Mol Cancer Ther. 2007 Jun;6(6):1785-92
17575107