Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells

Teru Hideshima, Laurence Catley, Hiroshi Yasui, Kenji Ishitsuka, Noopur Raje, Constantine Mitsiades, Klaus Podar, Nikhil C Munshi, Dharminder Chauhan, Paul G Richardson, Kenneth C Anderson

Research output: Journal article (peer-reviewed)Journal article

378 Citations (Scopus)

Abstract

Perifosine is a synthetic novel alkylphospholipid, a new class of antitumor agents which targets cell membranes and inhibits Akt activation. Here we show that baseline phosphorylation of Akt in multiple myeloma (MM) cells is completely inhibited by perifosine [octadecyl-(1,1-dimethyl-piperidinio-4-yl)-phosphate] in a time- and dose-dependent fashion, without inhibiting phosphoinositide-dependent protein kinase 1 phosphorylation. Perifosine induces significant cytotoxicity in both MM cell lines and patient MM cells resistant to conventional therapeutic agents. Perifosine does not induce cytotoxicity in peripheral blood mononuclear cells. Neither exogenous interleukin-6 (IL-6) nor insulinlike growth factor 1 (IGF-1) overcomes Perifosine-induced cytotoxicity. Importantly, Perifosine induces apoptosis even of MM cells adherent to bone marrow stromal cells. Perifosine triggers c-Jun N-terminal kinase (JNK) activation, followed by caspase-8/9 and poly (ADP)-ribose polymerase cleavage. Inhibition of JNK abrogates perifosine-induced cytotoxicity, suggesting that JNK plays an essential role in perifosine-induced apoptosis. Interestingly, phosphorylation of extracellular signal-related kinase (ERK) is increased by perifosine; conversely, MEK inhibitor synergistically enhances Perifosine-induced cytotoxicity in MM cells. Furthermore, perifosine augments dexamethasone, doxorubicin, melphalan, and bortezomib-induced MM cell cytotoxicity. Finally, perifosine demonstrates significant antitumor activity in a human plasmacytoma mouse model, associated with down-regulation of Akt phosphorylation in tumor cells. Taken together, our data provide the rationale for clinical trials of perifosine to improve patient outcome in MM.

Original languageEnglish
Pages (from-to)4053-4062
Number of pages10
JournalBlood
Volume107
Issue number10
DOIs
Publication statusPublished - 15 May 2006
Externally publishedYes

Keywords

  • Cell Division/drug effects
  • Cell Line, Tumor
  • Flow Cytometry
  • Growth Substances/pharmacology
  • Humans
  • Multiple Myeloma/pathology
  • Oncogene Protein v-akt/antagonists & inhibitors
  • Phosphorylation
  • Phosphorylcholine/analogs & derivatives

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