Mechanism of Cancer Growth Suppression of Alpha-Fetoprotein Derived Growth Inhibitory Peptides (GIP): Comparison of GIP-34 versus GIP-8 (AFPep). Updates and Prospects

Abstract

The Alpha-fetoprotein (AFP) derived Growth Inhibitory Peptide (GIP) is a 34-amino acid segment of the full-length human AFP molecule that inhibits tumor growth and metastasis. The GIP-34 and its carboxy-terminal 8-mer segment, termed GIP-8, were found to be effective as anti-cancer therapeutic peptides against nine different human cancer types. Following the uptake of GIP-34 and GIP-8 into the cell cytoplasm, each follows slightly different signal transduction cascades en route to inhibitory pathways of tumor cell growth and proliferation. The parallel mechanisms of action of GIP-34 versus GIP-8 are demonstrated to involve interference of signaling transduction cascades that ultimately result in: (1) cell cycle S-phase/G2-phase arrest; (2) prevention of cyclin inhibitor degradation; (3) protection of p53 from inactivation by phosphorylation; and (4) blockage of K+ ion channels opened by estradiol and epidermal growth factor (EGF). The overall mechanisms of action of both peptides are discussed in light of their differing modes of cell attachment and uptake fortified by RNA microarray analysis and electrophysiologic measurements of cell membrane conductance and resistance. As a chemotherapeutic adjunct, the GIPs could potentially aid in alleviating the negative side effects of: (1) tamoxifen resistance, uterine hyperplasia/cancer, and blood clotting; (2) Herceptin antibody resistance and cardiac (arrest) arrhythmias; and (3) doxorubicin's bystander cell toxicity.

The alpha-fetoprotein third domain receptor binding fragment: in search of scavenger and associated receptor targets

“…Computer modeling and molecular docking software As a first step for computer modeling and simulation, homology modeling was employed to produce a 3D structure of the human AFP based on a known human ALB model previously described [6,23]. Molecular docking sites on AFP were identified and localized by means of proprietary software (Peptimer Discovery Platform) generously provided by Serometrix LLC (Syracuse, NY).…”

“…Lastly, it is of interest that the AFP-derived Growth Inhibitory Peptide sequences (GIP-34, GIP-8) are located on AA #480 to 500, situated directly within the SR and SAR region [6,8,9,69,70]. Thus, it can be proposed that GIP-34 and GIP-8 bind largely to the scavenger receptors and to the mannose receptor.…”

“…This oncofetal protein is classified as a member of a three domain albuminoid protein family that currently consists of five members: albumin (ALB), vitamin-D binding protein (DBP), alpha-fetoprotein (AFP), alpha-albumin (alpha-ALB) and the AFP-related gene (ARG) protein [4]. Similar to ALB, HAFP binds and transports multiple ligands including bilirubin, fatty acids, retinoids, steroids, heavy metals, dyes, flavonoids, phytoestrogens, dioxins and various drugs [5,6]. Over the last two decades, reports have emerged showing that various forms of HAFP can serve as dual regulators of both fetal and tumor growth, either as growth enhancers or inhibitors [7,8].…”

Breast Cancer, Chemokines, And Metastasis: A Search for Decoy Ligands of the CXCR4 Receptor

“…However, unlike GIP, both P149c and AFPep lack significant anti-metastatic capabilities [38][39][40]. [38,39,46].…”

Cancer, circulating tumor cells, and metastasis: could protein-derived peptide fragments impede brain metastases?

“…It is of interest that, Serpin-I1 and plasminogen activator are known to promote cancer cell survival in brain metastasis by means of brain plasmin inhibition [28] . In the pro-inflammatory arena, AFP itself was found to interact and block CCR5 and CXCR4 chemokine receptors which are required for metastatic BC cell migration [29][30][31] .…”