Perifosine inhibits multiple signaling pathways in glial progenitors and cooperates with temozolomide to arrest cell proliferation in gliomas in vivo Journal Article

  

Authors:	Momota, H.; Nerio, E.; Holland, E. C.
Article Title:	Perifosine inhibits multiple signaling pathways in glial progenitors and cooperates with temozolomide to arrest cell proliferation in gliomas in vivo
Abstract:	Perifosine is an oral Akt inhibitor which exerts a marked cytotoxic effect on human tumor cell lines, and is currently being tested in several phase II trials for treatment of major human cancers. However, the efficacy of perifosine in human gliomas has not been established. As Akt is activated in ∼ 70% of human glioblastomas, we investigated the impact of perifosine on glia in culture and on a mouse glioma model in vivo. Here we show that perifosine strongly reduces phosphorylation levels of Akt and extracellular signal-regulated kinase (Erk) 1/2, induces cell cycle arrest in G1 and G2, and causes dose-dependent growth inhibition of mouse glial progenitors in which Akt and/or Ras-Erk 1/2 pathways are activated. Furthermore, because temozolomide is a common oral alkylating agent used in the treatment of gliomas, we investigated the effect of perifosine in combination with temozolomide. We observed an enhanced effect when both were used in culture. With these results, we combined perifosine and temozolomide as treatment of platelet-derived growth factor B-driven gliomas in mice. Animal studies showed that perifosine and temozolomide combination therapy was more effective than temozolomide treatment alone (P < 0.01). These results indicate that perifosine is an effective drug in gliomas in which Akt and Ras-Erk 1/2 pathways are frequently activated, and may be a new candidate for glioma treatment in the clinic. ©2005 American Association for Cancer Research.
Keywords:	signal transduction; mitogen activated protein kinase; protein kinase b; controlled study; human cell; proto-oncogene proteins; drug activity; dose response; drug potentiation; nonhuman; temozolomide; glioma; brain neoplasms; cell proliferation; mouse; animals; mice; dacarbazine; protein kinases; antineoplastic combined chemotherapy protocols; animal experiment; animal model; alkylating agent; in vivo study; cytotoxicity; dose-response relationship, drug; xenograft model antitumor assays; cell line, tumor; phosphorylation; mice, transgenic; stem cell; drug synergism; protein kinase inhibitors; protein-serine-threonine kinases; cell growth processes; platelet-derived growth factor; proto-oncogene proteins c-akt; glia cell; ras protein; cell cycle g2 phase; cell cycle g1 phase; g1 phase; perifosine; g2 phase; phosphorylcholine; cyclin-dependent kinase 2; cdc2-cdc28 kinases
Journal Title:	Cancer Research
Volume:	65
Issue:	16
ISSN:	0008-5472
Publisher:	American Association for Cancer Research
Date Published:	2005-08-15
Start Page:	7429
End Page:	7435
Language:	English
DOI:	10.1158/0008-5472.can-05-1042
PUBMED:	16103096
PROVIDER:	scopus
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-23844457178&partnerID=40&md5=b5d6b109ebe35ce7350c28f4dde2429b
Notes:	--- - "Cited By (since 1996): 96" - "Export Date: 24 October 2012" - "CODEN: CNREA" - "Source: Scopus"

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