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Author Notes:

Address correspondence and reprint requests to Donald G Stein, Department of Emergency Medicine, Brain Research Laboratory, 1365-B Clifton Road NE, Emory University, Atlanta, GA 30322. Phone: 404-712-2540; Fax: 404-727-2388; E-mail: donald.stein@emory.edu.

Subject:

Progesterone Inhibits the Growth of Human Neuroblastoma: In Vitro and In Vivo Evidence

Tools:

Journal Title:

Molecular Medicine

Volume:

Volume 17, Number 9-10

Publisher:

, Pages 1084-1094

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2011 The Feinstein Institute for Medical Research. Molecular Medicine is an open access journal. Anyone may copy, distribute, or reuse these articles as long as the author and original source are properly cited.

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