AFPep (alpha fetoprotein peptide) is an orally-active, cyclic, 9-

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A ...

with a molecular weight of 969 Daltons and is derived from the anti-

oncogenic Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...

active site (residues 472–479) of

alpha fetoprotein Alpha-fetoprotein (AFP, α-fetoprotein; also sometimes called alpha-1-fetoprotein, alpha-fetoglobulin, or alpha fetal protein) is a protein that in humans is encoded by the ''AFP'' gene. The ''AFP'' gene is located on the ''q'' arm of chromosome 4 ...

(AFP). Using the standard amino acid abbreviations, AFPep has the sequence ''cyclo''(EKTOVNOGN), where O is

hydroxyproline (2''S'',4''R'')-4-Hydroxyproline, or L-hydroxyproline ( C5 H9 O3 N), is an amino acid, abbreviated as Hyp or O, ''e.g.'', in Protein Data Bank. Structure and discovery In 1902, Hermann Emil Fischer isolated hydroxyproline from hydrolyzed gelatin. ...

. This peptide has been shown in experimental animal models to be efficacious in the prevention and treatment of ER+

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...

Biological activity

Background

Multiple births by a woman are strongly associated with a lower risk of developing

later in her life. One of the contributing factors for this association appears to be the

(AFP) produced by the fetal liver, which crosses the

placenta The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mater ...

and enters into the maternal circulation. Pregnancy-associated protection from breast cancer is directly proportional to level of exposure to AFP. Furthermore, it has been demonstrated that tumor growth can be inhibited by AFP in animal models of breast cancer. It is speculated that AFP may induce

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

in pre-malignant breast tissue cells which would have later developed into malignancies.

Anti cancer effects

Through mimicking the effects of AFP, AFPep inhibits the proliferation of

estrogen receptor Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen ( 17β-estradiol). Two classes of ER exist: nuclear estrogen receptors (ERα and ERβ), which are members of the ...

-positive human breast cancer cells growing in culture. It is also able to inhibit the estrogen stimulated growth of human breast cancer cells growing as

xenografts Xenotransplantation (''xenos-'' from the Greek meaning "foreign" or strange), or heterologous transplant, is the transplantation of living cells, tissues or organs from one species to another. Such cells, tissues or organs are called xenograft ...

in immunodeficient mice. According to a recent study, AFPep prevents the development of carcinogen-induced breast cancer in an animal model. Hence AFPep may have utility for preventing or treating estrogen receptor-positive breast cancer.

Mechanism of action

AFPep inhibits estrogen-stimulated growth of immature mouse uterus and thus is antiestrogenic. In culture, AFPep inhibits the

estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...

induced proliferation of T47D cells but has no effect on the basal growth. AFPep also inhibits

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

of the estrogen receptor and activates the phosphorylation of p53. AFPep has been shown to bind the

heat shock protein Heat shock proteins (HSP) are a family of proteins produced by cells in response to exposure to stressful conditions. They were first described in relation to heat shock, but are now known to also be expressed during other stresses including expo ...

Hsp72. Hsp72 together with

Hsp90 Hsp90 (heat shock protein 90) is a chaperone protein that assists other proteins to fold properly, stabilizes proteins against heat stress, and aids in protein degradation. It also stabilizes a number of proteins required for tumor growth, ...

form a heterocomplex with the

. Hence AFPep through interaction with Hsp72 controls the ligand binding and transcriptional activation of the estrogen receptor.

Combination therapy with tamoxifen

AFPep increases the efficacy and decreases the toxicities of

tamoxifen Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and treat breast cancer in women and men. It is also being studied for other types of cancer. It has b ...

. Tamoxifen has been a very effective drug for the treatment of estrogen receptor-positive breast cancer. But tamoxifen has certain toxicities and side effects such as uterine

hyperplasia Hyperplasia (from ancient Greek ὑπέρ ''huper'' 'over' + πλάσις ''plasis'' 'formation'), or hypergenesis, is an enlargement of an organ or tissue caused by an increase in the amount of organic tissue that results from cell proliferati ...

which can lead to endometrial cancer. Moreover, some breast cancers acquire resistance to tamoxifen during the course of treatment and few are totally resistant to it. It has been established that AFPep when used in combination with tamoxifen, reduces the uterine hyperplasia and increases the antitumour effects of tamoxifen. A rational combination of AFPep and tamoxifen may prove to be a better chemopreventive or chemotherapeutic approach against estrogen receptor-positive breast cancer.

Route of administration

AFPep active whether administered intraperitoneally, subcutaneously or orally.

References

{{Reflist, 2 Peptides