Introduction: Glioblastoma Multiforme (GBM) is the most frequent malignant primary tumor of the central nervous system. Patients with a diagnosis of glioblastoma have a poor prognosis despite advances in cancer treatment and surgical techniques. Consequently, new therapeutic agents are in demand for management. Recently, AFPep has been shown to have an effect on the proliferation, migration and invasion of glioblastoma cells. AFPep is a nine amino acid sequence cyclic analog of Alpha-fetoprotein (AFP), which is a glycoprotein produced during pregnancy by the fetal yolk sac and by fetal liver. AFPep is a peptide derived from a natural product and is well tolerated in animal studies. The data reported in this abstract showed a potential of development of AFPep for treatment of GBM.
Methods: AFPep was synthesized commercially . The anti-proliferative effect of APep was determined in MTT growth inhibition assay against cultured U87 human GBM. Chemotactic migration of GBM cells in response to serum was carried out by using a modified Boyden chamber assay and matrigel invasion assay. The in vivo anti-proliferative effect of AFPep was determined using human GBM xenografts growth assay using SCID mice.
Results: This study showed that AFPep inhibits the proliferation of cultured human glioblastoma cells in a dose-dependent manner with an IC50 of 1 nM. Tamoxifen also had a dose-dependent inhibitory effect with the IC50 of 5 µM. Treatment of SCID mice bearing U87 xenografts with 4 mg/Kg/day AFPep resulted in a significant inhibition of tumor growth. In addition, AFPep (10-6M to 10-4M) inhibited the invasion of U87 cells in a dose dependent manner in the Matrigel chemoinvasion assay.
Conclusions: The data reported here showed that AFPep inhibits the growth and invasion of human glioblastoma. Therefore, AFPep can be developed as chemotherapeutic agent for treatment of patients with GBM.
Patient Care: This is a basic science research with real potential of developing a novel therapeutic agent, AFPep for treatment of patients with glioblastoma.
Learning Objectives: By the conclusion of this session, participants should be able to:
1) Describe the importance and demand for new therapeutic agents for treatment patient with GBM
2) Discuss a potential development of novel agent AFPep for treatment of patients with GBM.
References: 1. Park M-J, Kim M-S, Park I-C, Kang H-S, Yoo H, Park SH, Rhee CH, Hong S-I, Lee S-H (2002) PTEN suppresses hyaluronic acid-induced matrix metalloproteinase-9 expression in U87MG glioblastoma cells through focal adhesion kinase dephosphorylation. Cancer Res 62:6318–6322
2. Golestaneh N, Mishra B (2005) TGF-beta, neuronal stem cells and glioblastoma. Oncogene 24:5722–5730
3. Puchner MJ, Herrmann HD, Berger J, Cristante L (2000) Surgery, tamoxifen, carboplatin, and radiotherapy in the treatment of newly diagnosed glioblastoma patients. J Neurooncol 49:147–155
4. Crandall BF (1981) Alpha-fetoprotein: a review. Crit Rev Clin Lab Sci 15:127–185
5. Bennett JA, DeFreest L, Anaka I, Saadati H, Balulad S, Jacobson HI, Andersen TT (2006) AFPep: an anti-breast cancer peptide that is orally active. Breast Cancer Res Treat 98:133–141
6. Andersen TT, Georgekutty J, DeFreest LA, Amaratunga G, Narendran A, Lemanski N, Jacobson HI, Bennett JA (2007) An a-fetoprotein-derived peptide reduces the uterine hyperplasia and increases the antitumour effect of tamoxifen. Br J Cancer 97:327–333
7. DeFreest LA (2005) Binding sites and mechanistic pathways for a novel human anti-breast cancer peptide. Thesis, Albany Medical College. 196-
8. Blume-Jensen P, Hunter T (2001) Oncogenic kinase signalling. Nature 411:355–365
9. Sihto H, Tynninen O, Bützow R, Saarialho-Kere U, Joensuu H (2007) Endothelial cell KIT expression in human tumours. J Pathol 211:481–488
10. Rutka JT, Muller M, Hubbard SL, et al (1999) Astrocytoma adhesion to extracellular matrix: functional significance of integrin and focal adhesion kinase expression. J Neuropathol Exp Neurol 58:198–209
11. Mesfin FB, Andersen TT, Friedlich D, Popp AJ, Jacobson HI, Bennett JA (2006) The effect of novel alpha-fetoprotein-derived peptide and tamoxifen on proliferation of cultured human glioblastoma cells. AACR Meeting Abstracts 2006:1113–c.
12. Mesfin FB, Bennett JA, Jacobson HI, Zhu S, Andersen TT (2000) Alpha-fetoprotein-derived antiestrotrophic octapeptide. Biochim Biophys Acta 1501:33–43
13. Mesfin FB, Andersen TT, Jacobson HI, Zhu S, Bennett JA (2001) Development of a synthetic cyclized peptide derived from alpha-fetoprotein that prevents the growth of human breast cancer. J Pept Res 58:246–256
14. Bennett JA, Pilon VA, MacDowell RT (1985) Evaluation of growth and histology of human tumor xenografts implanted under the renal capsule of immunocompetent and immunodeficient mice. Cancer Res 45:4963–4969
15. Bennett JA, Pilon VA, Briggs DR, McKneally MF (1985) Evaluation of cyclosporine-treated mice as hosts for growing and testing the chemosensitivity of first-transplant-generation human tumor xenografts implanted under the kidney capsule. J Natl Cancer Inst 75:925–936
16. Bennett JA, Zhu S, Pagano-Mirarchi A, Kellom TA, Jacobson HI (1998) Alpha-fetoprotein derived from a human hepatoma prevents growth of estrogen-dependent human breast cancer xenografts. Clin Cancer Res 4:2877–2884
17. Bennett JA, Pilon VA, Uppal GS, McKneally MF (1986) Accurate prediction of experimental cancer chemosensitivity using the subrenal capsule xenograft assay. J Surg Oncol 33:8–13