The Alpha-Fetoprotein–Derived Growth Inhibitory Peptide 8-Mer Fragment: Review of a Novel Anticancer Agent

Abstract

This review describes the antigrowth and anticancer activities of the alpha-fetoprotein (AFP)-derived growth inhibitory peptide (GIP) 8-mer fragment. The 8-amino acid peptide (GIP-8) comprises the carboxy-terminal portion of a 34-amino acid peptide (GIP-34) previously identified as an occult epitopic segment of the full-length human AFP molecule. The GIP-8 segment has been chemically synthesized, purified, characterized, and bioassayed. The purified 8-mer segment was characterized as a random coil (disordered) structure extending from a C-terminal β-hairpin that forms a horseshoe-shaped partially cyclic octapeptide; this structure can be formulated into a fully cyclic form by the addition of asparagine or glutamine residues. The pharmacophore of the octo- and nanopeptide forms is largely composed of a PXXP motif known to interact with Src-3 (SH3) domains of serine/theronine kinases. The GIP-8 has been shown to be growth-suppressive largely in estradiol (E2)-dependent neonatal and tumor-cell proliferation models and to inhibit tumor-cell adhesion to extracellular matrices. The 8-mer GIP displays antigrowth properties in immature mouse uterine cells and anticancer cell proliferation traits in estrogen receptor positive (ER⁺), but not (ER⁻) negative breast tumor cells. Even though its mechanism of action has not been fully elucidated, GIP-8 has been shown by computer modeling to dock with the extracellular loops of G-coupled seven transmembrane helical-like receptors, which could possibly interfere with signal transduction through MAP kinase pathways. It was apparent that the GIP-8 derived from the 34-mer GIP fragment of HAFP represented an E2-sensitive growth inhibitory motif, which allows the participation in cellular events, such as receptor binding, contact inhibition, extracellular matrix adhesion, angiogenesis, and T-cell activation. Thus, it was proposed that the 8-mer fragment derived from GIP could potentially serve as a lead compound for targeted cancer therapeutic agents of the biologic-response modifier type.