AFPep
Encyclopedia
AFPep is an orally active cyclic peptide with molecular weight of 969 Daltons
and is derived from the anti-oncogenic active site (residues 472-479) of alpha fetoprotein (AFP). Using the standard amino acid
abbreviations, AFPep has the sequence cyclo-(EKTOVNOGN), where O is hydroxyproline
. This peptide
has been shown in experimental animal models to be efficacious in the prevention and treatment of ER+ breast cancer
.
later in her life.
One of the contributing factors for this association appears to be α-fetoprotein
(AFP) produced by the fetal liver which crosses the placenta
and enters into the maternal circulation. Pregnancy-associated protection from breast cancer is directly proportional to exposure level 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
in pre-malignant breast tissue cells which would have later developed into malignancies.
-positive breast cancer.
induced proliferation of T47D cells but has no effect on the basal growth. AFPep also inhibits phosphorylation
of the estrogen receptor and activates the phosphorylation of p53.
AFPep has been shown to bind the heat shock protein
Hsp72
. Hsp72 together with Hsp90
form a heterocomplex with the estrogen receptor
. Hence AFPep through interaction with Hsp72 controls the ligand binding and transcriptional activation of the estrogen receptor.
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
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.
Molar mass
Molar mass, symbol M, is a physical property of a given substance , namely its mass per amount of substance. The base SI unit for mass is the kilogram and that for amount of substance is the mole. Thus, the derived unit for molar mass is kg/mol...
and is derived from the anti-oncogenic active site (residues 472-479) of alpha fetoprotein (AFP). Using the standard amino acid
Proteinogenic amino acid
Proteinogenic amino acids are those amino acids that can be found in proteins and require cellular machinery coded for in the genetic code of any organism for their isolated production. There are 22 standard amino acids, but only 21 are found in eukaryotes. Of the 22, 20 are directly encoded by...
abbreviations, AFPep has the sequence cyclo-(EKTOVNOGN), where O is hydroxyproline
Hydroxyproline
-4-Hydroxyproline, or L-hydroxyproline , is a common non-proteinogenic amino acid, abbreviated as HYP, e.g., in Protein Data Bank.-Structure and discovery:...
. This peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
has been shown in experimental animal models to be efficacious in the prevention and treatment of ER+ breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
.
Background
Multiple births by a woman are strongly associated with a lower risk of developing breast cancerBreast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
later in her life.
One of the contributing factors for this association appears to be α-fetoprotein
Alpha-fetoprotein
Alpha-fetoprotein is a protein that in humans is encoded by the AFP gene....
(AFP) produced by the fetal liver which crosses the placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
and enters into the maternal circulation. Pregnancy-associated protection from breast cancer is directly proportional to exposure level 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
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
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-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 in immune deficient 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 receptorEstrogen receptor
Estrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
-positive breast cancer.
Mechanism of action
AFPep inhibits estrogen-stimulated growth of immature mouse uterus and thus is antiestrogenic. In culture, AFPep inhibits the estrogenEstrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
induced proliferation of T47D cells but has no effect on the basal growth. AFPep also inhibits phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
of the estrogen receptor and activates the phosphorylation of p53.
AFPep has been shown to bind the heat shock protein
Heat shock protein
Heat shock proteins are a class of functionally related proteins involved in the folding and unfolding of other proteins. Their expression is increased when cells are exposed to elevated temperatures or other stress. This increase in expression is transcriptionally regulated...
Hsp72
HSPA1A
Heat shock 70 kDa protein 1 is a protein that in humans is encoded by the HSPA1A gene.-Interactions:HSPA1A has been shown to interact with ASK1, STUB1, MSR1, BAG3, Parkin , Fanconi anemia, complementation group C, GPR37, HSF1 and AIFM1....
. Hsp72 together with Hsp90
Hsp90
Hsp90 is a molecular chaperone and is one of the most abundant proteins expressed in cells. It is a member of the heat shock protein family, which is upregulated in response to stress...
form a heterocomplex with the estrogen receptor
Estrogen receptor
Estrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
. 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 TamoxifenTamoxifen
Tamoxifen
Tamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, hydroxytamoxifen. In other tissues such as the endometrium, it behaves as an agonist, hence tamoxifen may be characterized as a mixed agonist/antagonist...
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
Hyperplasia means increase in number of cells/proliferation of cells. It may result in the gross enlargement of an organ and the term is sometimes mixed with benign neoplasia/ benign tumor....
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.