We have successfully demonstrated, via dose response, that the Sisene drug (NOV/CCN3-CT) can block the growth of both primary and immortalized human endothelial cells while being ineffective in inhibiting the proliferation of normal/tumor epithelial cells. In addition, the Sisene compound was able to suppress endothelial cell tube formation and in vivo vascularization as assessed by the CAM assay. We have shown that the Sisene Rx inhibits adrenomedullin, apelin, SCNH2 mediated phosphorylation of PI3K/Akt and p44/42 MAPK pathways but not that of VEGF-A induced activation. Using biotinylated VEGF-A we have demonstrated that NOV/CCN3-CT does not block VEGF-A binding to HUVEC while slight suppressing (20%) of this angiogenic factors trophic ablitiy on the same target cell. Extending our analysis to pre-clinical studies using nude mouse xenograft models we have shown that NOV/CCN3-CT could block the growth of moderately vascularized human tumors cells (A549/Lung CA) with equivalent potency to the FDA approved anti-angiogenic Rx (Avastin) while being unresponsive with human tumors having high vessel density (ie HT1080/human fibroblast).
