SNS-032 Prevents Tumor Cell-Induced Angiogenesis By Inhibiting Vascular Endothelial Growth Factor

Abstract

Cell proliferation, migration, and capillary network formation of endothelial cells are the fundamental steps for angiogenesis, which involves the formation of new blood vessels. The purpose of this study is to investigate the effect of a novel aminothiazole SNS-032 on these critical steps for in vitro angiogenesis using a coculture system consisting of human umbilical vein endothelial cells (HUVECs) and human glioblastoma cells (U87MG). SNS-032 is a potent selective inhibitor of cyclin-dependent kinases 2, 7, and 9, and inhibits both transcription and cell cycle. In this study, we examined the proliferation and viability of HUVECs and U87MG cells in the presence of SNS-032 and observed a dose-dependent inhibition of cellular proliferation in both cell lines. SNS-032 inhibited threedimensional capillary network formations of endothelial cells. In a coculture study, SNS-032 completely prevented U87MG cell-mediated capillary formation of HUVECs. This inhibitor also prevented the migration of HUVECs when cultured alone or cocultured with U87MG cells. In addition, SNS-032 significantly prevented the production of vascular endothelial growth factor (VEGF) in both cell lines, whereas SNS-032 was less effective in preventing capillary network formation and migration of endothelial cells when an active recombinant VEGF was added to the medium. In conclusion, SNS-032 prevents in vitro angiogenesis, and this action is attributable to blocking of VEGF.

The cyclin-dependent kinase inhibitor SNS-032 has single agent activity in AML cells and is highly synergistic with cytarabine

“…Although these cell lines do not reflect the heterogeneity of the AML subgroups, they are informative about many aspects of the responses of AML cells to new agents. 35 Previously SNS-032 has been shown to have cell killing activity in glioblastoma 18 and CLL. 16 In the CLL study SNS-032 activity was found to be selective for CLL cells compared with non-malignant cells and its efficacy was not affected by patient characteristics, p53 status or fludarabine resistance making it potentially useful in refractory AML patients too.…”

“…17 The aim of drugs targeting CDKs is to inhibit cell proliferation, 9 but some of these new agents have also been shown to be potent inducers of apoptosis in cancer cells. 12 New CDK inhibitors, including SNS-032, are more selective and less cytotoxic 17,18 and have been shown to prolong stable disease in solid tumors. 7 In this study, we investigated the in vitro effects of SNS-032 in primary AML blasts and AML cell lines both as a single agent and in combination with cytarabine (Ara-C).…”

Mammalian Target of Rapamycin Pathway Promotes Tumor-Induced Angiogenesis in Adenoid Cystic Carcinoma: Its Suppression by Isoliquiritigenin through Dual Activation of c-Jun NH2-Terminal Kinase and Inhibition of Extracellular Signal-Regulated Kinase

“…Collection of ACC conditioned medium (CM) was performed as described previously (Ali et al, 2007) with minor modification. In brief, when ACC cells were grown to 70% confluence after overnight incubation, they were starved in serum-deprived DMEM for 12 h to obtain cell synchronization (Zhang and Peng, 2009).…”

Synergistic inhibition of angiogenesis and glioma cell-induced angiogenesis by the combination of temozolomide and enediyne antibiotic lidamycin

“…50 Briefly, C6 cells (2 × 10 5 cells/500 μl) cells were seeded to 24-well plate, 24 h later, the culture medium was replaced with fetal bovine serum (FBS)-free medium in the presence of LDM (0.1 nM) and TMZ (300 μM) alone or combination treatment. After 48 h incubation, 8-μm-pore size polyethylene tetraphthalate (PET) membrane inserts for 24-well plates (no matrigel coated) were located to the wells.…”