The activity of sunitinib against gastrointestinal stromal tumor seems to be distinct from its antiangiogenic effects

Memorial Sloan-Kettering Cancer Center, New York, New York, United States
Clinical Cancer Research (Impact Factor: 8.19). 11/2006; 12(20 Pt 1):6203-4. DOI: 10.1158/1078-0432.CCR-06-1292
Source: PubMed
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    ABSTRACT: Multi-target tyrosine kinase inhibitor Sunitinib has been widely used in cancer treatment, including metastatic renal cell carcinoma. However, most patients who initially benefit from Sunitinib develop resistance with extended usage of Sunitinib, which is referred to as "acquired resistance". The molecular mechanisms contributing to this acquired resistance remain poorly understood. In this present study, we established Sunitinib-resistant cell lines from human renal cell lines (786-O, A498, ACHN and CAKI1) by continuous treatment with Sunitinib to explore the molecular mechanism leading to Sunitinib resistance. We found that PDGFR-β expression in cell seems to be a protective factor against Sunitinib resistance formation. In addition, we found that both SK1 and ERK were activated in Sunitinib-resistance cell lines and SK1 and ERK inhibitors could resensitize Sunitinib-resistant cell lines. In conclusion, our observations suggest that SK1 and ERK activation is a feature of resistant cell lines, which serves as an alternative pathway evading anti-tumor activity of Sunitinib.
    Cell biochemistry and biophysics 08/2013; 68(2). DOI:10.1007/s12013-013-9723-4 · 3.34 Impact Factor
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    ABSTRACT: Nab-paclitaxel (NPT) has recently shown efficacy in pancreatic ductal adenocarcinoma (PDAC). Targeting tumor angiogenesis is a sensible combination therapeutic strategy for cancer including PDAC. We tested the hypothesis that nab-paclitaxel response in PDAC can be enhanced by the mechanistically different antiangiogenic agents, bevacizumab (Bev) or sunitinib (Su), despite its inherently increased tumor penetration and drug delivery. Compared to controls (19 days) median animal survival was increased after NPT therapy (32 days, a 68% increase, p<0.0008); other regimens with enhanced survival were NPT+Bev (38 days, a 100% increase, p<0.0004), NPT+Su (37 days, a 95% increase, p<0.0004) and NPT+Bev+Su (49 days, a 158% increase, p<0.0001) but not Bev, Su or Bev+Su therapy. Relative to controls (100±22.8), percent net local tumor growth was 28.2±23.4 with NPT, 55.6±18 (Bev), 38.8±30.2 (Su), 11±7.2 (Bev+Su), 32.8±29.2 (NPT+Bev), 6.6±10.4 (NPT+Su) and 13.8±12.5 (NPT+Bev+Su). Therapeutic effects on intratumoral proliferation, apoptosis, microvessel density and stromal density corresponded with tumor growth inhibition data. In AsPC-1 PDAC cells, nab-paclitaxel IC50 was reduced >6-fold by addition of sunitinib (IC25) but not by bevacizumab. In HUVEC endothelial cells, nab-paclitaxel IC50 (82 nM) was decreased to 41 nM by bevacizumab and to 63 nM by sunitinib. In fibroblast WI-38 cells, nab-paclitaxel IC50 (7.2 μM) was decreased to 7.8 nM by sunitinib, but not by bevacizumab. These findings suggest that the effects of one of the most active cytotoxic agents against PDAC, nab-paclitaxel, can be enhanced with antiangiogenic agents, which clinically could relate to greater responses and improved antitumor results.
    Molecular Cancer Therapeutics 03/2014; 13(5). DOI:10.1158/1535-7163.MCT-13-0361 · 5.60 Impact Factor
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    ABSTRACT: Sunitinib is an oral, small molecule multitargeted receptor tyrosine kinase inhibitor with antiangiogenic and antitumor activity that primarily targets vascular endothelial growth factor receptors (VEGFRs). Although sunitinib is an active agent for the treatment of malignant pheochromocytomas, it is unclear whether sunitinib acts through only antiangiogenic mechanisms or also directly targets tumor cells. We previously showed that sunitinib directly induced apoptosis of PC-12 cells. To further confirm these direct effects, we examined the effects of sunitinib on tyrosine hydroxylase (TH) (the rate-limiting enzyme in catecholamine biosynthesis) activity and catecholamine secretion in PC-12 cells and the underlying mechanisms. Sunitinib inhibited TH activity in a dose-dependent manner, and decreased TH protein levels. Consistent with this finding, sunitinib decreased TH phosphorylation at Ser(31) and Ser(40) and significantly decreased catecholamine secretion. VEGFR-2 knockdown attenuated these effects, including inhibition of TH activity and catecholamine secretion, suggesting that they were mediated by VEGFR-2. Sunitinib significantly decreased phospholipase C (PLC)-γ phosphorylation and subsequent protein kinase C (PKC) activity. Because Ser(40) phosphorylation significantly affects TH activity and is known to be regulated by PKC, sunitinib may inhibit Ser(40) phosphorylation via the VEGFR-2/PLC-γ/PKC pathway. Additionally, sunitinib markedly decreased the activity of extracellular signal-regulated kinase (ERK), but not c-Jun NH(2)-terminal kinase or p38 mitogen-activated protein kinase. Therefore, sunitinib may reduce TH Ser(31) phosphorylation through inhibition of the VEGFR-2/PLC-γ/PKC/Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/ERK pathway. Sunitinib also significantly reduced inositol 1,4,5-trisphosphate production. However, because PC-12 cells do not precisely reflect the pathogenesis of malignant cells, we confirmed the key findings in a human neuroblastoma cell line, SK-N-SH. In conclusion, sunitinib directly inhibits catecholamine synthesis and secretion in pheochromocytoma PC-12 cells.
    AJP Endocrinology and Metabolism 08/2012; 303(8):E1006-14. DOI:10.1152/ajpendo.00156.2012 · 4.51 Impact Factor


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