Combination of PI3K/mTOR inhibition demonstrates efficacy in human chordoma Journal Article

Authors: Schwab, J.; Antonescu, C.; Boland, P.; Healey, J.; Rosenberg, A.; Nielsen, P.; Iafrate, J.; Delaney, T.; Yoon, S.; Choy, E.; Harmon, D.; Raskin, K.; Yang, C.; Mankin, H.; Springfield, D.; Hornicek, F.; Duan, Z.
Article Title: Combination of PI3K/mTOR inhibition demonstrates efficacy in human chordoma
Abstract: Background: Chordomas are rare tumors of the axial skeleton for which surgical resection remains the most reliable means of cure. PI-103 is a inhibitor of PI3K/AKT and mTOR activation. This study aims to determine whether the PI3K/mTOR pathway was active in chordomas and whether their inhibition could lead to decreased proliferation and increased apoptosis. Materials and Methods: Thirteen human chordoma were tested for activation of the PI3K/mTOR pathway. The human chordoma cell line UCH-1 was treated with increasing doses of PI-103. Inhibition of AKT and mTOR was examined and assays assessing proliferation and apoptosis were performed. Results: The chordoma specimen demonstrated activation of the PI3K/mTOR pathway. PI-103 inhibited the AKT and mTOR activation in the UCH-1 cell line. PI-103 inhibited proliferation and induced apoptosis in UCH-1. Conclusion: The PI3K/AKT and mTOR signaling pathway is constitutively activated in chordoma. PI-103 decreases proliferation and induces apoptosis in the UCH-1 via inhibition of the PI3K/mTOR pathway.
Keywords: protein kinase b; controlled study; human tissue; human cell; cisplatin; doxorubicin; drug efficacy; drug potentiation; antineoplastic agents; pyridines; cell proliferation; apoptosis; enzyme inhibition; protein kinases; in vitro study; tumor cells, cultured; pyrimidines; phosphatidylinositol 3 kinase; protein kinase inhibitors; cancer inhibition; blotting, western; cancer cell; mammalian target of rapamycin; 1-phosphatidylinositol 3-kinase; proto-oncogene proteins c-akt; upregulation; drug cytotoxicity; antibiotics, antineoplastic; chordoma; concentration response; pi3k; mtor; furans; pi-103; 2 (4 hydroxyphenyl) 4 morpholinopyrido[3',2':4,5]furo[3,2 d]pyrimidine; phosphoinositide dependent protein kinase 1
Journal Title: Anticancer Research
Volume: 29
Issue: 6
ISSN: 0250-7005
Publisher: International Institute of Anticancer Research  
Date Published: 2009-01-01
Start Page: 1867
End Page: 1871
Language: English
PUBMED: 19528441
PROVIDER: scopus
Notes: --- - "Cited By (since 1996): 1" - "Export Date: 30 November 2010" - "CODEN: ANTRD" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Patrick J Boland
    151 Boland
  2. Cristina R Antonescu
    769 Antonescu
  3. John H Healey
    497 Healey