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

Mizejewski GJ - Cancers (Basel) (2011)

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus

A flow diagram showing the proposed mechanism of growth inhibition of cancer cells by GIP-34 (left side) and GIP-8 (right side). Solid black-line arrows indicate pathways verified by direct evidence; the dash-line arrows represent hypothetical, proposed, or published pathways.
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f3-cancers-03-02709: A flow diagram showing the proposed mechanism of growth inhibition of cancer cells by GIP-34 (left side) and GIP-8 (right side). Solid black-line arrows indicate pathways verified by direct evidence; the dash-line arrows represent hypothetical, proposed, or published pathways.

Mentions: The biological activities of GIP are cataloged and listed in chronological order in Table 1. The secondary structure analysis of GIP-34 revealed an amphipathic peptide consisting of 45% beta sheets and turns, 45% random coil (disorder) and 10% alpha-helix [13-15,25]. GIP-34 displays a carboxyl-terminal type-I reverse beta turn as does the 8-mer peptide [26,27]. This type of beta-turn has been demonstrated to enhance the biological activity of ligand binding to cell surface receptors; such studies revealed that this receptor topology is known to preferentially accommodate the beta-turn in ligand-to-receptor binding kinetics [26]. GIP-34 has been shown to bind to the plasma membrane of human MCF-7 breast cancer cells and concomitant pulse-chase experiments indicated that this contact resulted in rapid cell internalization of the peptide within 1–5 min [19,28]. The peptide undergoes subsequent transmembrane passage into the cytosol and within 1.0 h the peptide is observed in a diffusely scattered pattern throughout the cytosol; by 2.0 h the peptide is trafficked to the perinuclear region of the endoplasmic reticulum, an area which immediately surrounds the nucleus [19]. In addition, evidence obtained from electrophysiologic Sharp microelectrode whole cell recordings of MCF-7 tumor cells was obtained using glass micropipettes filled with 3 M potassium acetate and 0.1 M potassium chloride with an inserted chloridized silver wire. Membrane potential was recorded at room temperature with an Axoclamp 2A (Axon Instruments) multifunction amplifier in constant current mode. Membrane resistance was determined by passing 70 msec 200 pA hyperpolarizing constant current square-wave pulses at 280 msec intervals, measuring the corresponding voltage deflections and applying Ohm's law. In vivo recordings indicated that GIP-34, at 10−6 M and lower concentrations serves as a cell membrane pore forming/cell penetrating peptide coincident with decreased cell membrane resistance; at high peptide concentrations (10−5 M and greater) GIP-34 acts as a channel blocker coincident with increased cell membrane resistance [28] (Figure 2). Patch clamp experiments also confirmed that low concentrations of GIP produced decreased membrane resistance (pore-forming). The pore-forming/cell penetrating molecules have been shown to be amphipathic peptides of >20 AAs and resemble the antimicrobial peptides which are discussed below [29]. In contrast, a channel blocker is a drug or peptide that interacts at the plasma membrane in juxtaposition to an ion channel nestled among a macromolecular cluster of signaling proteins (signalplex) on the inner side of the cell membrane [30]. Thus, GIP-34 can gain entrance into cancer cells by at least two pathways namely, (a) receptor-mediated endocystosis and (b) pore-forming/cell penetration (Figure 3).


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

Mizejewski GJ - Cancers (Basel) (2011)

A flow diagram showing the proposed mechanism of growth inhibition of cancer cells by GIP-34 (left side) and GIP-8 (right side). Solid black-line arrows indicate pathways verified by direct evidence; the dash-line arrows represent hypothetical, proposed, or published pathways.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757439&req=5

f3-cancers-03-02709: A flow diagram showing the proposed mechanism of growth inhibition of cancer cells by GIP-34 (left side) and GIP-8 (right side). Solid black-line arrows indicate pathways verified by direct evidence; the dash-line arrows represent hypothetical, proposed, or published pathways.
Mentions: The biological activities of GIP are cataloged and listed in chronological order in Table 1. The secondary structure analysis of GIP-34 revealed an amphipathic peptide consisting of 45% beta sheets and turns, 45% random coil (disorder) and 10% alpha-helix [13-15,25]. GIP-34 displays a carboxyl-terminal type-I reverse beta turn as does the 8-mer peptide [26,27]. This type of beta-turn has been demonstrated to enhance the biological activity of ligand binding to cell surface receptors; such studies revealed that this receptor topology is known to preferentially accommodate the beta-turn in ligand-to-receptor binding kinetics [26]. GIP-34 has been shown to bind to the plasma membrane of human MCF-7 breast cancer cells and concomitant pulse-chase experiments indicated that this contact resulted in rapid cell internalization of the peptide within 1–5 min [19,28]. The peptide undergoes subsequent transmembrane passage into the cytosol and within 1.0 h the peptide is observed in a diffusely scattered pattern throughout the cytosol; by 2.0 h the peptide is trafficked to the perinuclear region of the endoplasmic reticulum, an area which immediately surrounds the nucleus [19]. In addition, evidence obtained from electrophysiologic Sharp microelectrode whole cell recordings of MCF-7 tumor cells was obtained using glass micropipettes filled with 3 M potassium acetate and 0.1 M potassium chloride with an inserted chloridized silver wire. Membrane potential was recorded at room temperature with an Axoclamp 2A (Axon Instruments) multifunction amplifier in constant current mode. Membrane resistance was determined by passing 70 msec 200 pA hyperpolarizing constant current square-wave pulses at 280 msec intervals, measuring the corresponding voltage deflections and applying Ohm's law. In vivo recordings indicated that GIP-34, at 10−6 M and lower concentrations serves as a cell membrane pore forming/cell penetrating peptide coincident with decreased cell membrane resistance; at high peptide concentrations (10−5 M and greater) GIP-34 acts as a channel blocker coincident with increased cell membrane resistance [28] (Figure 2). Patch clamp experiments also confirmed that low concentrations of GIP produced decreased membrane resistance (pore-forming). The pore-forming/cell penetrating molecules have been shown to be amphipathic peptides of >20 AAs and resemble the antimicrobial peptides which are discussed below [29]. In contrast, a channel blocker is a drug or peptide that interacts at the plasma membrane in juxtaposition to an ion channel nestled among a macromolecular cluster of signaling proteins (signalplex) on the inner side of the cell membrane [30]. Thus, GIP-34 can gain entrance into cancer cells by at least two pathways namely, (a) receptor-mediated endocystosis and (b) pore-forming/cell penetration (Figure 3).

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus