Cardiac hormones are dual inhibitors of vascular endothelial growth factor and the VEGFR2 receptor
J P Nguyen1, C D Frost2, M L Lane2, W P Skelton3, M Skelton2 & D L Vesely2
Introduction: The growth of human tumors depends on the formation of new blood vessels and vascular endothelial growth factor (VEGF) helps control this process via inducing new capillaries to sprout from pre-existing blood vessels. Four cardiac hormones which eliminate up to 80% of human pancreatic cancers and up to 86% of human small-cell lung cancers growing in mice were investigated for their effects on VEGF and the VEGFR2/KDR/Flk-1 receptor. The VEGFR2 receptor is the main receptor mediating VEGFs cancer enhancing effects.
Methods: The cardiac hormones effects on VEGF/VEGFR2 levels in three human cancer cell lines were measured by ELISAs.
Results: These four cardiac hormones, i.e. vessel dilator, long-acting natriuretic peptide (LANP), kaliuretic peptide, and atrial natriuretic peptide (ANP) over a concentration range of 100 pM to 10 μM maximally decreased the VEGFR2 receptor in human pancreatic adenocarcinoma cells by 48, 49, 74, and 83%. Vessel dilator, LANP, kaliuretic peptide, and ANP decreased the VEGFR2 receptor by 77, 89, 88, and 67%, respectively in human small-cell lung cancer cells. Maximal decrease of VEGFR2 receptor in human prostate cancer cells by vessel dilator, LANP, kaliuretic peptide, and ANP was 48, 92, 64, and 71%. VEGF itself in human pancreatic carcinoma cells was decreased by 42, 58, 36, and 40% respectively, by vessel dilator, LANP, kaliuretic peptide and ANP. In small-cell lung cancer cells, the maximal decrease in VEGF levels was 25, 23, 17 and 23% secondary to vessel dilator, LANP, kaliuretic peptide, and ANP. In human prostate cancer cells, VEGF was maximally decreased 24, 20, 23, and 24% secondary to vessel dilator, LANP, kaliuretic peptide, and ANP respectively.
Conclusion: Four cardiac hormones are the first dual inhibitors of VEGF and the VEGFR2/KDR/Flk-1 receptor.
COI Details: Dr Vesely has assigned the patent to treat cancer with these cardiac hormones to the University of South Florida, which has not licensed this patent to any commercial entity. There has been no pharmaceutical company funding or input into the studies described herein. The contents of this publication do not represent the views of the Department of Veterans Affairs or the United States Government. None of the other authors has any potential conflict of interest.
Funding Details: This work was supported in part by grants from the James and Esther King Florida Biomedical Research Program, the Florida Department of Health, and the Mama Mare Foundation.