Targeted Anticancer Drug Sorafenib Impairs Vascular Network Formation by Human Cardiac Microvascular Endothelial Cells

Sorafenib is a novel multikinase inhibitor drug that is approved for the treatment of renal cell carcinoma and hepatocellular carcinoma, and is being tested in other common types of cancers. Recent clinical trials revealed that the use of this agent is associated with such cardiovascular complications as hypertension and reduced left ventricular ejection fraction. Sorafenib is known to inhibit Raf kinase, as well as VEGFR2 and PDGF receptor tyrosine kinase activities. We set out to test the hypothesis that sorafenib suppresses cardiac endothelial functions and angiogenesis. We treated human cardiac microvascular endothelial cells (HCMVEC) with VEGF, FGF2, and PDGF-BB in order to examine effects of sorafenib on signaling pathways activated by these pro-angiogenic factors. We determined in these studies that VEGFR2 tyrosine kinase was the most sensitive target of sorafenib in human cardiac endothelial cells. As a result, sorafenib inhibited proliferation and viability of HCMVEC. In order to examine effects of sorafenib on cardiac angiogenesis, we used a co-culture assay of HCMVEC with human cardiac fibroblasts. Sorafenib suppressed the formation of vascular networks in this in vitro assay with an IC50 of approximately 30 nM. In an in vivo Matrigel plug assay, VEGF and FGF2 were admixed into Matrigel before injecting it to mice in order to induce vascular growth within the plug. Control plugs exhibited robust development of vascular networks while sorafenib (daily injections of 30 mg/kg) severely inhibited vascular growth within the plugs. Taken together, this data provide the evidence that endothelial cells present a viable target of sorafenib in the heart.