Some studies have reported that VEGFR-1 inhibition is not sufficient read FAQ to block tumor growth without combined inhibition of VEGFR-2.28,29 In addition, it is unclear if VEGFR-1 inhibitors, by preventing the binding of VEGF to VEGFR-1, increase the concentration of free VEGF that can subsequently activate VEGFR-2 and stimulate angiogenesis by an alternate pathway. The precise mechanisms of VEGFR-1 inhibitor functioning warrant further exploration.26 We demonstrated that HIF-1�� expressions increase in association with elevated PlGF. HIF-1�� and TUBB3 were upregulated in hypoxia and became more induced in response to PlGF treatment. We also demonstrated that inhibition of VEGFR-1 is associated with decreases in HIF-1�� and TUBB3 expression. Calvani, et al.
18 reported that VEGFR-2, rather than VEGFR-1, mediates VEGF-dependent induction of HIF-1�� in hypoxic HCT116 colon cancer cells, suggesting that functional VEGFR-2, but not functional VEGFR-1, exists in this colon cancer cell line. Cell viability assay results demonstrated that AGS cell cytotoxicity was most pronounced when cells were treated simultaneously with paclitaxel, anti-VEGFR-1, and anti-VEGFR-2. Through these results, we suggest that AGS cells express functional VEGFR-1 and VEGFR-2. TUBB3 confers chemoresistance to taxanes. Our experiment results of paclitaxel resistance in AGS cells are consistent with other reports suggesting that TUBB3 affects chemoresistance to taxanes in diverse cancer cells.12-16 Raspaglio, et al.21 also reported that TUBB3 is not only a parameter related to the chemoresponsiveness, but also could be a pure prognostic marker.
TUBB3 expression levels differ by cell and tissue types. In some tissues, TUBB3 is constitutively expressed and is not inducible upon hypoxia.21 In AGS cells, we observed TUBB3 was constitutively expressed in normoxia and became more induced in hypoxia. The present study demonstrated that blockade of both VEGFR-1 and VEGFR-2 in conjunction with paclitaxel synergistically depresses induction of HIF-1�� and TUBB3 expression, and more effectively increases cytotoxicity in gastric cancer cells. ACKNOWLEDGEMENTS This study was supported by a grant (CRI11073-1) Chonnam national university hospital research institute of clinical medicine. Footnotes The authors have no financial conflicts of interest.
In 1990, the Centers for Disease Control and Prevention (CDC) reported the first documented outbreak of 26 Carfilzomib cases of acute hepatitis B virus (HBV) infections in the United States that was attributed to reuse of fingerstick devices for capillary blood sampling on multiple patients [1]. Public health authorities identified that nursing staff on an inpatient hospital ward had performed blood glucose monitoring on successive patients without changing disposable lancet end-caps between each patient.