title: Progesterone inhibits the growth of human neuroblastoma: in vitro and in vivo evidence.
abstract: We investigated the antitumorogenic effects of progesterone (P4) in a human neuroblastoma (SK-N-AS) cell line in vitro and in a mouse xenograft model of neuroblastoma. The safety of P4 was tested in rat primary cortical neurons and human foreskin fibroblasts (HFF-1). At high doses, P4 significantly (P < 0.05) decreased SK-N-AS cell viability in vitro, and this effect was not blocked either by 5α-reductase inhibitor, finasteride or the P4 receptor antagonist RU486. Even at very high doses, P4 did not induce any cell death in healthy primary cortical neurons or HFF-1. The bioavailability of P4 24 h after the last injection in the serum of treated animals was significantly (P < 0.05) higher (10-33 μg/mL) than in untreated animals. In nude mice, P4 (50 and 100 mg/kg) inhibited neuroblastoma growth by ~50% over 8 d of treatment. No drug toxicity was observed in the mice, as measured by body weight and activity. P4 suppressed the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP-9, MMP-2), which are involved in tumor vascular development. High-dose P4 inhibited tumor growth by suppressing cell proliferation and inducing apoptosis, as evidenced by the expression of proliferating cell nuclear antigen and cleaved caspase-3. P4 significantly increased the expression of P4 receptor isoform-A and suppressed phospho-Akt (Ser437) expression. In conclusion, at high doses, P4 effectively inhibits the growth of solid neuroblastoma tumor and has high bioavailability, selective toxicity and a high margin of safety, making it a possible candidate for further study as a potential clinical treatment of neuroblastoma.
authors.affiliation: Departments of Emergency Medicine Brain Research Laboratory, Emory University, Atlanta, Georgia, USA.
authors.forename: Fahim
authors.initials: F
authors.lastname: Atif
authors.forename: Iqbal
authors.initials: I
authors.lastname: Sayeed
authors.forename: Seema
authors.initials: S
authors.lastname: Yousuf
authors.forename: Tauheed
authors.initials: T
authors.lastname: Ishrat
authors.forename: Fang
authors.initials: F
authors.lastname: Hua
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Brat
authors.forename: Donald G
authors.initials: DG
authors.lastname: Stein
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018120:Finasteride / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D015735:Mifepristone / Q000494:pharmacology; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011374:Progesterone / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D058891:5-alpha Reductase Inhibitors; D006727:Hormone Antagonists; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D015735:Mifepristone; D011374:Progesterone; D018120:Finasteride; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9