Abstract
Angiogenesis is critical and indispensable for tumor progression. Since VEGF is known to play a central role in angiogenesis, the disruption of VEGF-VEGF receptor system is a promising target for anti-cancer therapy. Previously, we reported that a hexapeptide (RRKRRR, RK6) blocked the growth and metastasis of tumor by inhibiting VEGF binding to its receptors. In addition, dRK6, the D-form derivative of RK6, retained its biological activity with improved serum stability. In the present study, we developed a serum-stable branched dimeric peptide (MAP2-dRK6) with enhanced anti-VEGF and anti-tumor activity. MAP2-dRK6 is more effective than dRK6 in many respects: inhibition of VEGF binding to its receptors, VEGF- and tumor conditioned medium-induced proliferation and ERK signaling of endothelial cells, and VEGF-induced migration and tube formation of endothelial cells. Moreover, MAP2-dRK6 blocks in vivo growth of VEGF-secreting colorectal cancer cells by the suppression of angiogenesis and the subsequent induction of tumor cell apoptosis. Our observations suggest that MAP2-dRK6 can be a prospective therapeutic molecule or lead compound for the development of drugs for various VEGF-related angiogenic diseases.
Highlights
Angiogenesis, the sprouting of new blood vessels from pre-existing vasculature, occurs during embryonic development and physiological processes such as wound healing and formation of the female reproductive system in a highly controlled manner by coordination of various pro- and anti-angiogenic factors (Liotta et al, 1991; Carmeliet, 2000)
We previously reported that a VEGF-binding hexapeptide (RRKRRR, RK6) identified by screening peptide library antagonizes the activity of VEGF, resulting in the inhibition of the growth and metastasis of VEGF-secreting tumor (Bae et al, 2000)
A VEGF-binding hexapeptide RK6 inhibited the binding of VEGF to its receptors (Bae et al, 2000), and dRK6, its derivative composed of D-amino acids, showed increased serum stability with similar activity in the inhibition of VEGF binding to receptors (Yoo et al, 2005)
Summary
Angiogenesis, the sprouting of new blood vessels from pre-existing vasculature, occurs during embryonic development and physiological processes such as wound healing and formation of the female reproductive system in a highly controlled manner by coordination of various pro- and anti-angiogenic factors (Liotta et al, 1991; Carmeliet, 2000). The balance between these factors is lost in pathological conditions like rheumatoid arthritis, diabetic retinopathy, and especially cancer, resulting in abnormal and inadequate growth of blood vessels (Carmeliet and Jain, 2000). Among numerous pro-angiogenic factors, VEGF is known to be specific to endothelial cells and critical for angiogenesis (Yancopoulos et al, 2000). VEGF is a homodimeric glycoprotein that exerts its activity via binding to two receptors, VEGF receptor (VEGFR1) and VEGFR2, expressed on the surface of endothelial cells (de Vries et al, 1992; Millauer et al, 1993). Anti-angiogenic approaches for cancer treatment by disrupting VEGF-VEGFR system have been attempted (Kim et al, 1992; Aiello et al, 1995; Borgstrom et al, 1996; Strawn et al, 1996)
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