Synthesis of Glycolysis Inhibitor PFK15 and Its Synergistic Action with an Approved Multikinase Antiangiogenic Drug on Human Endothelial Cell Migration and Proliferation.
Jana ZlackáMiroslav MurárGabriela AddováRoman MoravčíkAndrej BoháčMichal ZemanPublished in: International journal of molecular sciences (2022)
Activated endothelial, immune, and cancer cells prefer glycolysis to obtain energy for their proliferation and migration. Therefore, the blocking of glycolysis can be a promising strategy against cancer and autoimmune disease progression. Inactivation of the glycolytic enzyme PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase) suppresses glycolysis level and contributes to decreased proliferation and migration of cancer (tumorigenesis) and endothelial (angiogenesis) cells. Recently, several glycolysis inhibitors have been developed, among them ( E )-1-(pyridin-4-yl)-3-(quinolin-2-yl)prop-2-en-1-one (PFK15) that is considered as one of the most promising. It is known that PFK15 decreases glucose uptake into the endothelial cells and efficiently blocks pathological angiogenesis. However, no study has described sufficiently PFK15 synthesis enabling its general availability. In this paper we provide all necessary details for PFK15 preparation and its advanced characterization. On the other hand, there are known tyrosine kinase inhibitors (e.g., sunitinib), that affect additional molecular targets and efficiently block angiogenesis. From a biological point of view, we have studied and proved the synergistic inhibitory effect by simultaneous administration of glycolysis inhibitor PFK15 and multikinase inhibitor sunitinib on the proliferation and migration of HUVEC. Our results suggest that suppressing the glycolytic activity of endothelial cells in combination with growth factor receptor blocking can be a promising antiangiogenic treatment.
Keyphrases
- endothelial cells
- growth factor
- high glucose
- vascular endothelial growth factor
- cell migration
- papillary thyroid
- signaling pathway
- multiple sclerosis
- renal cell carcinoma
- squamous cell
- emergency department
- type diabetes
- young adults
- blood pressure
- metabolic syndrome
- metastatic renal cell carcinoma
- cell proliferation
- tyrosine kinase
- oxidative stress
- single molecule
- skeletal muscle
- childhood cancer
- protein kinase
- endoplasmic reticulum stress
- replacement therapy
- smoking cessation
- induced pluripotent stem cells
- tandem mass spectrometry