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

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2013 Nov 12

PMID 24212829

Citations 8

Authors

Gerald J Mizejewski

Affiliations

Soon will be listed here.

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.

Citing Articles

The Role of Ion Channels and Chemokines in Cancer Growth and Metastasis: A Proposed Mode of Action Using Peptides in Cancer Therapy.

Mizejewski G Cancers (Basel). 2024; 16(8).

PMID: 38672613 PMC: 11048196. DOI: 10.3390/cancers16081531.

The Role of Alpha-Fetoprotein (AFP) in Contemporary Oncology: The Path from a Diagnostic Biomarker to an Anticancer Drug.

Glowska-Ciemny J, Szymanski M, Kuszerska A, Malewski Z, von Kaisenberg C, Kocylowski R Int J Mol Sci. 2023; 24(3).

PMID: 36768863 PMC: 9917199. DOI: 10.3390/ijms24032539.

AFP-Inhibiting Fragments for Drug Delivery: The Promise and Challenges of Targeting Therapeutics to Cancers.

Lin B, Dong X, Wang Q, Li W, Zhu M, Li M Front Cell Dev Biol. 2021; 9:635476.

PMID: 33898423 PMC: 8061420. DOI: 10.3389/fcell.2021.635476.

Alpha-Fetoprotein Binding Mucin and Scavenger Receptors: An Available Bio-Target for Treating Cancer.

Lin B, Wang Q, Liu K, Dong X, Zhu M, Li M Front Oncol. 2021; 11:625936.

PMID: 33718192 PMC: 7947232. DOI: 10.3389/fonc.2021.625936.

Elucidating Binding Sites and Affinities of ERα Agonists and Antagonists to Human Alpha-Fetoprotein by In Silico Modeling and Point Mutagenesis.

Moldogazieva N, Ostroverkhova D, Kuzmich N, Kadochnikov V, Terentiev A, Porozov Y Int J Mol Sci. 2020; 21(3).

PMID: 32019136 PMC: 7036865. DOI: 10.3390/ijms21030893.

References

Mizejewski G . Biological roles of alpha-fetoprotein during pregnancy and perinatal development. Exp Biol Med (Maywood). 2004; 229(6):439-63. DOI: 10.1177/153537020422900602. View

Cantor R . Size distribution of barrel-stave aggregates of membrane peptides: influence of the bilayer lateral pressure profile. Biophys J. 2002; 82(5):2520-5. PMC: 1302042. DOI: 10.1016/S0006-3495(02)75595-1. View

Hua S, Chen S, Lu C, Kao Y, Yu H, Chen P . The effects of growth inhibitory peptide on follicular thyroid cancer cell growth, migration, and invasion. Tumori. 2010; 96(3):448-51. DOI: 10.1177/030089161009600312. View

Butterstein G, MacColl R, Mizejewski G, Eisele L, Meservey M . Biophysical studies and anti-growth activities of a peptide, a certain analog and a fragment peptide derived from alpha-fetoprotein. J Pept Res. 2003; 61(4):213-8. DOI: 10.1034/j.1399-3011.2003.00049.x. View

Strobl J, Wonderlin W, Flynn D . Mitogenic signal transduction in human breast cancer cells. Gen Pharmacol. 1995; 26(8):1643-9. DOI: 10.1016/0306-3623(95)00062-3. View

Butterstein G, Morrison J, Mizejewski G . Effect of alpha-fetoprotein and derived peptides on insulin- and estrogen-induced fetotoxicity. Fetal Diagn Ther. 2003; 18(5):360-9. DOI: 10.1159/000071981. View

Mizejewski G . Review of the putative cell-surface receptors for alpha-fetoprotein: identification of a candidate receptor protein family. Tumour Biol. 2010; 32(2):241-58. DOI: 10.1007/s13277-010-0134-5. View

Vollmer Jr C, Eilber F, Butterfield L, Ribas A, Dissette V, Koh A . Alpha-fetoprotein-specific genetic immunotherapy for hepatocellular carcinoma. Cancer Res. 1999; 59(13):3064-7. View

Kirschner K, Lexa K, Salisburg A, Alser K, Joseph L, Andersen T . Computational design and experimental discovery of an antiestrogenic peptide derived from alpha-fetoprotein. J Am Chem Soc. 2007; 129(19):6263-8. PMC: 4272344. DOI: 10.1021/ja070202w. View

10.

Monen S, Schmidt P, Wondergem R . Membrane potassium channels and human bladder tumor cells. I. Electrical properties. J Membr Biol. 1998; 161(3):247-56. DOI: 10.1007/s002329900331. View

11.

Butterfield L, Ribas A, Dissette V, Lee Y, Yang J, de la Rocha P . A phase I/II trial testing immunization of hepatocellular carcinoma patients with dendritic cells pulsed with four alpha-fetoprotein peptides. Clin Cancer Res. 2006; 12(9):2817-25. DOI: 10.1158/1078-0432.CCR-05-2856. View

12.

Marino A, Iliev I, Schwalke M, Gonzalez E, Marler K, Flanagan C . Association between cell membrane potential and breast cancer. Tumour Biol. 1994; 15(2):82-9. DOI: 10.1159/000217878. View

13.

Mizejewski G, Dias J, Hauer C, Henrikson K, Gierthy J . Alpha-fetoprotein derived synthetic peptides: assay of an estrogen-modifying regulatory segment. Mol Cell Endocrinol. 1996; 118(1-2):15-23. DOI: 10.1016/0303-7207(96)03762-8. View

14.

Sabourin J, Cognard C, Constantin B . Regulation by scaffolding proteins of canonical transient receptor potential channels in striated muscle. J Muscle Res Cell Motil. 2010; 30(7-8):289-97. DOI: 10.1007/s10974-010-9206-9. View

15.

Mizejewski G . The alpha-fetoprotein-derived growth inhibitory peptide 8-mer fragment: review of a novel anticancer agent. Cancer Biother Radiopharm. 2007; 22(1):73-98. DOI: 10.1089/cbr.2006.343. View

16.

Butterfield L, Ribas A, Potter D, Economou J . Spontaneous and vaccine induced AFP-specific T cell phenotypes in subjects with AFP-positive hepatocellular cancer. Cancer Immunol Immunother. 2007; 56(12):1931-43. PMC: 11030770. DOI: 10.1007/s00262-007-0337-9. View

17.

Mesfin F, Bennett J, Jacobson H, Zhu S, Andersen T . Alpha-fetoprotein-derived antiestrotrophic octapeptide. Biochim Biophys Acta. 2000; 1501(1):33-43. DOI: 10.1016/s0925-4439(00)00008-9. View

18.

Mizejewski G . Biological role of alpha-fetoprotein in cancer: prospects for anticancer therapy. Expert Rev Anticancer Ther. 2002; 2(6):709-35. DOI: 10.1586/14737140.2.6.709. View

19.

Nahta R, Takahashi T, Ueno N, Hung M, Esteva F . P27(kip1) down-regulation is associated with trastuzumab resistance in breast cancer cells. Cancer Res. 2004; 64(11):3981-6. DOI: 10.1158/0008-5472.CAN-03-3900. View

20.

Suzuki K, Oda Y, Oda K, Tanaka S, Sakaino Y, Matsudaira T . Non-genomic action of 17beta-estradiol on opening of Ca(2+)- and voltage-activated K+ channel in lacrimal acinar cells. Tokai J Exp Clin Med. 2004; 29(3):71-8. View