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Perifosine inhibits Akt and induces cytotoxicity in human multiple myeloma cells

07-17-2006

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

According to a study from the United States, "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-d imethyl-piperidinio-4-yl)-phosphate] in a time- and dose-dependent fashion, without inhibiting phosphoinositide-dependent protein kinase 1 phosphorylation."

T. Hideshima and colleagues at the Dana Farber Cancer Institute found, "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 mono-nuclear cells. Neither exogenous interleukin-6 (IL-6) nor insulin-like growth factor 1 (IGF-1) overcomes Perifosine-induced cytotoxicity."

"Importantly," discovered investigators, "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 downregulation of Akt phosphorylation in tumor cells."

The researchers concluded, "[O]ur data provide the rationale for clinical trials of perifosine to improve patient outcome in MM."

Hideshima and colleagues published the results of their research in Blood (Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood, 2006;107(10):4053-4062).

For additional information, contact K.C. Anderson, Dana Farber Cancer Institute, Jerome Lipper Multiple Myeloma Center, Dept. Med Oncology, Mayer 557, 44 Binney St., Boston, MA 02115, USA.

The publisher of the journal Blood can be contacted at: American Society Hematology, 1900 M Street. NW Suite 200, Washington, DC 20036, USA.

Keywords: Boston, Massachusetts, United States, Alternative Medicine, Anticancer Therapy, Antitumor Activity, Apoptosis, Bone Marrow, Clinical Trial, Conventional Therapies, Doxorubicin, Multiple Myeloma, Oncology, Peripheral Blood, Perifosine, Cytotoxicity, Alkylphospholipid, Akt.

This article was prepared by Clinical Oncology Week editors from staff and other reports. Copyright 2006, Clinical Oncology Week via NewsRx.com.