Perifosine

Biological Activity

Perifosine is a novel p.o. bioavailable alkylphospholipid. Perifosine has displayed significant antiproliferative activity in vitro and in vivo in several human tumor model systems and has recently entered phase I clinical trials. Perifosine causes dose-dependent inhibition of protein kinase B/Akt phosphorylation and thus activation at concentrations causing growth inhibition of PC-3 prostate carcinoma cells. Only the myristoylated form of Akt (MYR-Akt), which bypasses the requirement for pleckstrin homology (PH) domain-mediated membrane recruitment, abrogated perifosine-mediated decrease of Akt phosphorylation and cell growth inhibition by perifosine. Perifosine decreases the plasma membrane localization of Akt, and this is substantially relieved by MYR-Akt along with relief of downstream compound effect on induction of p21(WAF1/CIP1). Perifosine does not directly affect phosphoinositide 3-kinase (PI3K), phosphoinositide-dependent kinase 1, or Akt activity at concentrations inhibiting Akt phosphorylation and membrane localization.

Product Citations

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  J Hepatol . 2022 Nov 9;S0168-8278(22)03285-8.

  Hepatocyte-specific Mas activation enhances lipophagy and fatty acid oxidation to protect against acetaminophen-induced hepatotoxicity in mice
  Perifosine purchased from AbMole

• 

  Front Oncol. 2021 Apr 1;11:649176.

  Akt Inhibition Enhanced the Growth Inhibition Effects of Low-Dose Heavy-Ion Radiation via the PI3K/Akt/p53 Signaling Pathway in C6 Glioblastoma Cells
  Perifosine purchased from AbMole

• 

  Drυg Discοv Ther. 2020 Sep 8;14(4):197-203.

  MicroRNA analysis of NCI-60 human cancer cells indicates that miR-720 and miR-887 are potential therapeutic biomarkers for breast cancer
  Perifosine purchased from AbMole

Customer Product Validations & Biological Datas

	Source	Drug Discoveries & Therapeutics 2020. Figure 4. perifosine (Abmole Bioscience Inc, Houston, TX, USA)
	Method	MTT assay
	Cell Lines	A549, H460, H322M, MCF-7, T47-D and MDA-MB-231 cells
	Concentrations	-
	Incubation Time	72 h
	Results	The current study verified that the anti-cancer effect of perifosine was significantly enhanced by inhibiting miR-720 and that the anti-cancer effect of 5-Fu was significantly enhanced by inhibiting miR-887 in breast cancer cells

Protocol (for reference only)

Cell Experiment
Cell lines	MM cells
Preparation method	Growth inhibition assay. The inhibitory effect of perifosine, alone or combined with other agents, on MM cell growth was assessed by measuring 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrasodium bromide (MTT; Chemicon International, Temecula, CA) dye absorbance. Cells were pulsed with 10 μL of 5 mg/mL MTT to each well for the last 4 hours of 24-hour and/or 48-hour cultures, followed by 100 μL isopropanol containing 0.04 N HCl. Absorbance was measured at 570/630 nm using a spectrophotometer (Molecular Devices, Sunnyvale, CA).
Concentrations	0~100 μM
Incubation time	24 or 48 h

Animal Experiment
Animal models	MM.1S cells xenograft model in Immunodeficient BNX mice
Formulation	0.9% sodium chloride
Dosages	daily (36 mg/kg) or weekly (250 mg/kg)
Administration	oral

Chemical Information

Molecular Weight	461.66
Formula	C25H52NO4P
CAS Number	157716-52-4
Solubility (25°C)	Water 50 mg/mL
Storage	Powder          -20°C   3 years ;  4°C   2 years In solvent       -80°C   6 months ;  -20°C   1 month

Conversion of different model animals based on BSA (PMID: 27057123)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

References

[1] Richardson PG, et al. Expert Opin Drug Metab Toxicol. Perifosine , an oral, anti-cancer agent and inhibitor of the Akt pathway: mechanistic actions, pharmacodynamics, pharmacokinetics, and clinical activity.

[2] Lin X, et al. Neoplasma. Perifosine downregulates MDR1 gene expression and reverses multidrug-resistant phenotype by inhibiting PI3K/Akt/NF-κB signaling pathway in a human breast cancer cell line.

[3] Richardson PG, et al. J Clin Oncol. Perifosine plus bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma previously treated with bortezomib: results of a multicenter phase I/II trial.

[4] Hideshima T, et al. Blood. Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells.