Dual blockade of VEGFR1 and VEGFR2 by a novel peptide abrogates VEGF-driven angiogenesis, tumor growth, and metastasis through PI3K/AKT and MAPK/ERK1/2 pathway.

BACKGROUND: Neutralization of vascular endothelial growth factor receptor 1 (VEGFR1) and/or VEGFR2 is a widely used means of inhibiting tumor angiogenesis. METHODS: Based on the complex X-ray structures of VEGFA/VEGFR1, VEGFA/VEGFR2, and VEGFB/VEGFR1, a peptide (referred to as VGB) was designed to simultaneously bind to VEGFR1 and VEGFR2, and binding, antiangiogenic and antitumor properties of the peptide was investigated in vitro. RESULTS: VGB bound to both VEGFR1 and VEGFR2 in human umbilical vein endothelial cells (HUVECs) and 4 T1 mammary carcinoma tumor (MCT) cells, and inhibited the proliferation of HUVE, 4 T1 MCT, and U87 glioblastoma cells. Through abrogation of AKT and ERK1/2 phosphorylation, VEGFA-stimulated proliferation, migration, and two- and three-dimensional tube formation in HUVECs were inhibited more potently by VGB than by bevacizumab. In a murine 4 T1 MCT model, VGB strongly inhibited tumor growth without causing weight loss, accompanied by inhibition of AKT and ERK1/2 phosphorylation, a significant decrease in tumor cell proliferation (Ki-67 expression), angiogenesis (CD31 and CD34 expression), an increase in apoptosis index (increased TUNEL staining and p53 expression and decreased Bcl-2 expression), and the suppression of systematic spreading of the tumor (reduced NF-κB and MMP-9 and increased E-cadherin expression). CONCLUSION: The dual specificity of VGB for VEGFR1 and VEGFR2, through which the PI3K/AKT and MAPK/ERK1/2 signaling pathways can be abrogated and, subsequently, angiogenesis, tumor growth, and metastasis are inhibited. GENERAL SIGNIFICANCE: This study demonstrated that simultaneous blockade of VEGFR1 and VEGFR2 downstream cascades is an effective means for treatment of various angiogenic disorders, especially cancer.

The relationship between immediate preoperative serum 25-hydroxy-vitamin D3 levels and cardiac function, dysglycemia, length of stay, and 30-d readmissions in cardiac surgery patients.

OBJECTIVES: Vitamin D has pleiotropic effects on cardiac, renal, and endocrine diseases like diabetes mellitus and deficiency has been correlated with increased Intensive Care Unit (ICU) morbidity and mortality. We studied the relationship between preoperative Vitamin D levels and several short-term endpoints including cardiovascular events, glucose levels, ICU, and hospital length of stay. METHODS: Standard demographic data were obtained. Blood samples were drawn for 25-hydroxy-vitamin D3 (Vit D) levels at baseline (just before induction of anesthesia) and on postoperative day (POD #1). The number of inotropes used on POD # 0, 1, and 2 was recorded as well as the Cardiac Index (CI). Baseline glucose, Blood Urea Nitrogen and Creatinine (Cr) levels were obtained and repeated on POD # 1 & 2. Other variables studied are number of days of ICU and hospital stay. RESULTS: Of the 64 patients included in the cohort, 3 were excluded because of inadequate data. 69% had Vit D levels <20 ng/mL and 31% had levels ≥20 ng/mL. More than 90% of the cohort had a significant decrease in POD # 1 Vit D levels (P < 0.001). Age, sex, race, and body mass index did not predict the preoperative Vit D levels; however, the timing of surgery was associated with preoperative Vit D levels, lowest in subjects who had surgery performed during winter. Preoperative Vit D levels had no effect on postoperative glycemic control, cardiac index, or composite outcome-arrhythmias, respiratory failure, or prolonged inotropic support. On regression analysis, preoperative Vit D levels did show a significant effect on ICU and hospital length of stay in this cohort. CONCLUSIONS: The low levels in this study truly represent the Vit D status as they were obtained before any intervention, including surgery or fluid administration. Vit D levels decreased rapidly after surgery and hence future studies on Vit D may need to focus on premorbid levels obtained at the time of initial presentation and not those obtained after resuscitation or ICU admission. In contrast to epidemiologic reports, we found no association between low Vit D levels and postoperative cardiovascular events. However, low Vit D levels did affect the ICU and hospital length of stay in patients who were undergoing cardiac surgery. This is an important finding especially when many institutions and regulatory agencies are investigating novel therapies and processes to reduce the length of hospitalization. More studies are required to investigate the effect on hospital length of stay of early preadmission or preoperative Vit D supplementation before elective surgery.