Effect of SU11248 on gastrointestinal stromal tumor-T1 cells: enhancement of growth inhibition via inhibition of 3-kinase/Akt/mammalian target of rapamycin signaling.
SU11248 is an orally available type III and V receptor tyrosine kinase inhibitor. Clinical studies have shown the efficacy of SU11248 in individuals with gastrointestinal stromal tumors (GIST); however, the molecular mechanisms by which SU11248 inhibits the proliferation of these tumor cells remains to be fully elucidated. Taking advantage of GIST-T1 cells, which possess an activating mutation in exon 11 of the c-KIT gene, we examined the medicinal action of SU11248 in GIST cells. Clonogenic and MTT assays showed that SU11248 potently inhibited the proliferation of GIST-T1 cells with IC50 of approximately 1 nM and 40 nM, respectively. SU11248 (10 or 20 nM, 48 h) activated caspase-3 and induced apoptosis of GIST-T1 cells as measured by caspase assay, annexin V staining and cleavage of poly (ADP-ribose) polymerase. Western blot analyses found that SU11248 blocked autophosphorylation of c-KIT in association with inhibition of its downstream effectors, including Akt and extracellular signal-regulated kinase, but not signal transducers and activators of transcription. Interestingly, when phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling was blocked simultaneously by either LY294002 or rapamycin, growth inhibition mediated by SU11248 was potentiated. Taken together, this study supports clinical studies of SU11248 for individuals with GIST, and the combination of SU11248 and inhibitors of 3-kinase/Akt/mammalian target of rapamycin signaling represents a promising novel treatment strategy.
Ikezoe
Takayuki
T
Department of Hematology and Respiratory Medicine, Graduate School of Kuroshio Science, Kochi University, Nankoku, Kochi 783-8505, Japan. ikezoet@med.kochi-u.ac.jp
Yang
Yang
Y
Nishioka
Chie
C
Bandobashi
Kentaro
K
Nakatani
Hajime
H
Taguchi
Takahiro
T
Koeffler
H Phillip
HP
Taguchi
Hirokuni
H
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology; D010770:Phosphotransferases / Q000187:drug effects; D011494:Protein Kinases / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000187:drug effects; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D020123:Sirolimus / Q000494:pharmacology; D000077210:Sunitinib; D058570:TOR Serine-Threonine Kinases
D000970:Antineoplastic Agents; D002867:Chromones; D004791:Enzyme Inhibitors; D007211:Indoles; D009025:Morpholines; D011758:Pyrroles; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D010770:Phosphotransferases; D011494:Protein Kinases; C546842:MTOR protein, human; D019009:Proto-Oncogene Proteins c-kit; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D000077210:Sunitinib; D020123:Sirolimus