Anti-tumor effects of progesterone in human glioblastoma multiforme: role of PI3K/Akt/mTOR signaling.
Glioblastoma multiforme (GBM) is an aggressive primary brain tumor with a mean patient survival of 13-15 months despite surgical resection, radiation therapy and standard-of-care chemotherapy. We investigated the chemotherapeutic effects of the hormone progesterone (P4) on the growth of human GBM in four genetically different cell lines (U87MG, U87dEGFR, U118MG, LN-229) in vitro and in a U87MG subcutaneous xenograft mouse model. At high concentrations (20, 40, and 80 μM), P4 significantly (P<0.05) decreased tumor cell viability in all cell lines except LN-229. This effect was not blocked by the P4 receptor antagonist RU468. Conversely, at low physiological concentrations (0.1, 1, and 5 μM) P4 showed a proliferative effect in all cell lines which was blocked by RU486. In nude mice, P4 (100 and 200 mg/kg) inhibited tumor growth significantly (P<0.05) over 5 weeks of treatment and extended survival time of tumor-bearing mice by 60% without signs of systemic toxicity. P4 suppressed tumor vascularization as indicated by the expression of CD31, vascular endothelial growth factor and matrix metalloproteinase-9. Apoptosis in tumor tissue was detected by the expression of cleaved caspase-3, BCl-2, BAD and p53 proteins and confirmed by TUNEL assay. P4 treatment also suppressed PI3K/Akt/mTOR signaling, which regulates tumor growth, as demonstrated by the suppression of proliferating cell nuclear antigen. Our data can be interpreted to suggest that P4 suppresses the growth of human GBM cells both in vitro and in vivo and enhances survival time in mice without any demonstrable side effects. This article is part of a Special Issue entitled 'Sex steroids and brain disorders'.
Department of Emergency Medicine, Brain Research Laboratory, Emory University, Atlanta, GA 30322, USA. Electronic address: fatif@emory.edu.
Fahim
F
Atif
Department of Emergency Medicine, Brain Research Laboratory, Emory University, Atlanta, GA 30322, USA.
Seema
S
Yousuf
Department of Emergency Medicine, Brain Research Laboratory, Emory University, Atlanta, GA 30322, USA.
Donald G
DG
Stein
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008819:Mice, Nude; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011374:Progesterone / Q000008:administration & dosage / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D020780:Matrix Metalloproteinase 9; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011374:Progesterone; D051057:Proto-Oncogene Proteins c-akt; D011980:Receptors, Progesterone; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A; C467484:VEGFA protein, human; C546842:MTOR protein, human; C494929:PTEN protein, human
Glioblastoma; Progesterone; Treatment; Tumor