AFPep

AFPep (alpha fetoprotein peptide) is an orally-active, cyclic, 9-amino acid, peptide with a molecular weight of 969 Daltons and is derived from the anti-oncogenic active site (residues 472–479) of alpha fetoprotein (AFP).[1] 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.[2]

Biological activity

Background

Multiple births by a woman are strongly associated with a lower risk of developing breast cancer later in her life.[3] One of the contributing factors for this association appears to be the alpha fetoprotein (AFP) produced by the fetal liver, which crosses the placenta and enters into the maternal circulation.[4] Pregnancy-associated protection from breast cancer is directly proportional to level of exposure to AFP.[5] Furthermore, it has been demonstrated that tumor growth can be inhibited by AFP in animal models of breast cancer.[6][7] It is speculated that AFP may induce apoptosis in pre-malignant breast tissue cells which would have later developed into malignancies.[3]

Anti cancer effects

Through mimicking the effects of AFP, AFPep inhibits the proliferation of estrogen receptor-positive human breast cancer cells growing in culture.[8] It is also able to inhibit the estrogen stimulated growth of human breast cancer cells growing as xenografts in immunodeficient mice.[8] According to a recent study, AFPep prevents the development of carcinogen-induced breast cancer in an animal model.[9] 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.[1] In culture, AFPep inhibits the estrogen induced proliferation of T47D cells but has no effect on the basal growth.[10] AFPep also inhibits phosphorylation of the estrogen receptor and activates the phosphorylation of p53.[10]

AFPep has been shown to bind the heat shock protein Hsp72.[11] 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.

Combination therapy with tamoxifen

AFPep increases the efficacy and decreases the toxicities of tamoxifen.

Tamoxifen has been a very effective drug for the treatment of estrogen receptor-positive breast cancer. But tamoxifen has certain toxicities and side effects[12][13][14] 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.[2] A rational combination of AFPep and tamoxifen may prove to be a better chemopreventive or chemotherapeutic approach against estrogen receptor-positive breast cancer.[2]

Route of administration

AFPep active whether administered intraperitoneally, subcutaneously or orally.[10]

References
  1. Mesfin FB, Bennett JA, Jacobson HI, Zhu S, Andersen TT (April 2000). "Alpha-fetoprotein-derived antiestrotrophic octapeptide". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1501 (1): 33–43. doi:10.1016/S0925-4439(00)00008-9. PMID 10727847.
  2. Andersen TT, Georgekutty J, Defreest LA, Amaratunga G, Narendran A, Lemanski N, Jacobson HI, Bennett JA (August 2007). "An alpha-fetoprotein-derived peptide reduces the uterine hyperplasia and increases the antitumour effect of tamoxifen". British Journal of Cancer. 97 (3): 327–33. doi:10.1038/sj.bjc.6603882. PMC 2360332. PMID 17637684.
  3. Jacobson HI, Thompson WD, Janerich DT (May 1989). "Multiple births and maternal risk of breast cancer". American Journal of Epidemiology. 129 (5): 865–73. doi:10.1093/oxfordjournals.aje.a115220. PMID 2641667.
  4. Crandall BF; Lau, H. Lonin (1981). "Alpha-fetoprotein: a review". Critical Reviews in Clinical Laboratory Sciences. 15 (2): 127–85. doi:10.3109/10408368109105870. PMID 6169490.
  5. Richardson BE, Hulka BS, Peck JL, Hughes CL, van den Berg BJ, Christianson RE, Calvin JA (October 1998). "Levels of maternal serum alpha-fetoprotein (AFP) in pregnant women and subsequent breast cancer risk". American Journal of Epidemiology. 148 (8): 719–27. doi:10.1093/oxfordjournals.aje.a009691. PMID 9786226.
  6. Sonnenschein C, Ucci AA, Soto AM (May 1980). "Growth inhibition of estrogen-sensitive rat mammary tumors. Effect of an alpha-fetoprotein-secreting hepatoma". Journal of the National Cancer Institute. 64 (5): 1147–52. doi:10.1093/jnci/64.5.1147. PMID 6154169.
  7. Bennett JA, Zhu S, Pagano-Mirarchi A, Kellom TA, Jacobson HI (November 1998). "Alpha-fetoprotein derived from a human hepatoma prevents growth of estrogen-dependent human breast cancer xenografts". Clinical Cancer Research. 4 (11): 2877–84. PMID 9829755.
  8. DeFreest LA, Mesfin FB, Joseph L, McLeod DJ, Stallmer A, Reddy S, Balulad SS, Jacobson HI, Andersen TT, Bennett JA (May 2004). "Synthetic peptide derived from alpha-fetoprotein inhibits growth of human breast cancer: investigation of the pharmacophore and synthesis optimization". The Journal of Peptide Research. 63 (5): 409–19. doi:10.1111/j.1399-3011.2004.00139.x. PMID 15140158.
  9. Parikh RR, Gildener-Leapman N, Narendran A, Lin HY, Lemanski N, Bennett JA, Jacobson HI, Andersen TT (December 2005). "Prevention of N-methyl-N-nitrosourea-induced breast cancer by alpha-fetoprotein (AFP)-derived peptide, a peptide derived from the active site of AFP". Clinical Cancer Research. 11 (23): 8512–20. doi:10.1158/1078-0432.CCR-05-1651. PMID 16322315.
  10. Bennett JA, DeFreest L, Anaka I, Saadati H, Balulad S, Jacobson HI, Andersen TT (July 2006). "AFPep: an anti-breast cancer peptide that is orally active". Breast Cancer Research and Treatment. 98 (2): 133–41. doi:10.1007/s10549-005-9140-5. PMID 16538538.
  11. DeFreest L, Bennett J (2004-05-01). "Identification of Cellular Binding Sites for a Novel Human Anti-Breast Cancer Peptide". Storming Media. Retrieved 2008-11-09.
  12. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N (September 1998). "Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study". Journal of the National Cancer Institute. 90 (18): 1371–88. doi:10.1093/jnci/90.18.1371. PMID 9747868.
  13. Assikis VJ, Jordan VC (June 1995). "Gynecologic effects of tamoxifen and the association with endometrial carcinoma". International Journal of Gynaecology and Obstetrics. 49 (3): 241–57. doi:10.1016/0020-7292(95)02387-R. PMID 9764862.
  14. Kraft JK, Hughes T (February 2006). "Polypoid endometriosis and other benign gynaecological complications associated with Tamoxifen therapy-a case to illustrate features on magnetic resonance imaging". Clinical Radiology. 61 (2): 198–201. doi:10.1016/j.crad.2005.09.007. PMID 16439226.
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