Uses
An alkylphospholipid which inhibits Akt activation and the anti-apoptotic MAPK pathway.
Uses
It acts as an Akt inhibitor and a PI3K inhibitor, and is a drug candidate being developed for a variety of cancer indications.
Definition
ChEBI: A phospholipid consisting of 1,1-dimethylpiperidinium-4-yl hydrogen phosphate in which the hydrogen is replaced by a stearyl (octadecyl) group.
Biological Activity
perifosine is an inhibitor of akt [1].perifosine is a synthetic antitumor alkylphospholipid. it induces cell apoptosis through inhibiting the activity of akt. perifosine shows antitumor activity in various cell lines including nsclc, mm, epithelial carcinoma, prostate carcinoma and leukemia cells. in h460 cells, perifosine decreased cell survival and induced apoptosis with ic50 values of 1μm and 10 μm, respectively. the treatment of perifosine was also found to induce cleavage of caspase-8, caspase-9, caspase-3 and parp in this cell line. in mm.1s cells, perifosine induced sub-g1 phase population increase from 15% to 57% at 10 μm and induced cleavage of caspase-8, caspase-9 and parp in a dose-dependent manner. in mice inoculated with mm.1s cells, oral administration of perifosine significantly reduced mm tumor growth and increased survival [1, 2].
Biochem/physiol Actions
Perifosine (octadecyl-(1,1-dimethyl-4-piperidylio)) is an antitumor compound. It acts at lipid rafts and stops lysosomal accumulation and mTORC1 (mammalian target of rapamycin complex 1) signaling. This drug exhibits significant antiproliferative activity in vitro and in vivo in various human cancer model systems.
Enzyme inhibitor
This novel Akt signal-transduction pathway inhibitor (F.Wt. = 461.66; CAS
157716-52-4; Solubility (25°C) : <1 mg/mL DMSO, 8 mg/mL Water), also
known as KRX-0401 and 1,1-dimethylpiperidinium-4-yl octadecyl
phosphate (zwitterion), inhibits Akt protein kinases, IC50 = 5 μM. Perifosine
strongly inhibits Akt and extracellular signal-regulated kinase (Erk) 1/2,
inducing cell cycle arrest in G1 and G2, as well as dose-dependent growth
inhibition of mouse glial progenitors. Perifosine (10 μM) completely
inhibits Akt in MM.1S cells and induces cell cycle arrest and apoptosis
in human hepatocellular carcinoma cell lines, again by inhibiting Akt
phosphorylation. Note: Perifosine is related structurally to miltefosine.
References
[1] elrod h a, lin y d, yue p, et al. the alkylphospholipid perifosine induces apoptosis of human lung cancer cells requiring inhibition of akt and activation of the extrinsic apoptotic pathway. molecular cancer therapeutics, 2007, 6(7): 2029-2038.
[2] hideshima t, catley l, yasui h, et al. 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.
