Small Molecule Inhibitors of Tumor-Promoted Angiogenesis, Including Protein Tyrosine Kinase Inhibitors

Hamby, James M.; Showalter, Hollis D.

doi:10.1016/s0163-7258(98)00053-9

Cited by 66 publications

(33 citation statements)

References 130 publications

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“…Sorafenib and Rottlerin Reduce Cell Migration. Tumor cell migration and invasion is a characteristic feature of malignant gliomas, typically associated with pathological vascularization (Folkman, 1971;Hamby and Showalter, 1999). Given the contribution of VEGF signaling and PKC to this invasive phenotype (Cho et al, 1999;da Rocha et al, 2000), we questioned whether signaling inhibition with sorafenib and rottlerin might inhibit this process in vitro.…”

mentioning

confidence: 99%

Coadministration of Sorafenib with Rottlerin Potently Inhibits Cell Proliferation and Migration in Human Malignant Glioma Cells

Jane

Premkumar

Pollack

2006

The Journal of Pharmacology and Experimental Therapeutics

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Mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) are activated in the majority of gliomas and contribute to tumor cell growth and survival. Sorafenib (Bay43-9006; Nexavar) is a dual-action Raf and vascular endothelial growth factor receptor inhibitor that blocks receptor phosphorylation and MAPK-mediated signaling and inhibits growth in a number of tumor types. Because our initial studies of this agent in a series of glioma cell lines showed only partial growth inhibition at clinically achievable concentrations, we questioned whether inhibition of PKC signaling using the PKC-␦ inhibitor rottlerin might potentiate therapeutic efficacy. Proliferation assays, apoptosis induction studies, and Western immunoblot analysis were conducted in cells treated with sorafenib and rottlerin as single agents or in combination. Sorafenib and rottlerin reduced proliferation in all cell lines when used as single agents, and the combination produced marked potentiation of growth inhibition. Flow-cytometric measurements of cells stained with Annexin V-propidium iodide and immunocytochemical assessment of cytochrome c and apoptosis-inducing factor release demonstrated that addition of rottlerin resulted in significantly higher levels of apoptosis than sorafenib alone. In addition, the combination of sorafenib and rottlerin reduced or completely inhibited the phosphorylation of extracellular signal-regulated kinase and Akt and down-regulated cell cycle regulatory proteins such as cyclin-D1, cyclin-D3, cyclin-dependent kinase (cdk)4, and cdk6 in a dose-and time-dependent manner. Our results clearly indicate that inhibition of PKC-␦ signaling enhances the antiproliferative effect of sorafenib in malignant human glioma cell lines and support the examination of combinations of signaling inhibitors in these tumors.

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confidence: 99%

Coadministration of Sorafenib with Rottlerin Potently Inhibits Cell Proliferation and Migration in Human Malignant Glioma Cells

Jane

Premkumar

Pollack

2006

The Journal of Pharmacology and Experimental Therapeutics

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“…There are multiple tyrosine kinase receptors which appear to have key roles in the generation of new tumor blood vessels and, as such, represent reasonable targets for cancer chemotherapy (for excellent recent reviews, see Randal, 2000;Thompson et al, 1999;Hamby and Showalter, 1999). Included among the key tyrosine kinase targets that have generated the most interest in the scienti®c and patent (Connell, 2000) literature are PDGFR, VEGFR, FGFR and tie-2.…”

Section: Small Molecule Tyrosine Kinase Inhibitors Targeting Angiogenmentioning

confidence: 99%

From oncogene to drug: development of small molecule tyrosine kinase inhibitors as anti-tumor and anti-angiogenic agents

Morin

2000

Oncogene

114

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“…For example, elevated expression of vascular endothelial growth factor, epidermal growth factor, fibroblast growth factor and platelet derived growth factor are associated with tumor angiogenesis, metastases, survival and resistance to apoptosis. Therefore, these growth factors have represented potential molecular targets for inhibition of tumor growth and progression [1][2][3][4] . In addition, data accumulate that significant levels of cross talk exists within and between signalling networks in most tumours, necessitating the combined inhibition of multiple targets in order to establish efficient tumour growth inhibition.…”

Section: Introductionmentioning

confidence: 99%

Quinazoline-sulfonamides as potential antitumor agents: synthesis and biological testing

Alafeefy

Alqasoumi

Ashour

et al. 2012

Journal of Enzyme Inhibition and Medicinal Chemistry

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Small Molecule Inhibitors of Tumor-Promoted Angiogenesis, Including Protein Tyrosine Kinase Inhibitors

Cited by 66 publications

References 130 publications

Coadministration of Sorafenib with Rottlerin Potently Inhibits Cell Proliferation and Migration in Human Malignant Glioma Cells

Coadministration of Sorafenib with Rottlerin Potently Inhibits Cell Proliferation and Migration in Human Malignant Glioma Cells

From oncogene to drug: development of small molecule tyrosine kinase inhibitors as anti-tumor and anti-angiogenic agents

Quinazoline-sulfonamides as potential antitumor agents: synthesis and biological testing

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