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 over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...

with a molecular weight of 969

dalton Dalton may refer to: Science * Dalton (crater), a lunar crater * Dalton (program), chemistry software * Dalton (unit) (Da), a.k.a. unified atomic mass unit * John Dalton, chemist, physicist and meteorologist * 12292 Dalton, an asteroid Ent ...

s 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 ...

(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 gela ...

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

breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...

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 (: placentas or placentae) 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 ...

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 ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

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 proteins found in cell (biology), cells that function as receptor (biochemistry), receptors for the hormone estrogen (17β-estradiol). There are two main classes of ERs. The first includes the intracellular estrogen ...

-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. 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 (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...

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

phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...

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

heat shock protein Heat shock proteins (HSPs) 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 ex ...

Hsp72. Hsp72 together with

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

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 men. It is also being studied for other types of cancer. It has been used for Albright syndrome ...

. 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 Tissue (biology), organic tissue that results from ...

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 Nonapeptides Cyclic peptides