Perifosine as a potent Akt inhibitor

by Selleckchem | Oct 15 2012

FEATURES OF PERIFOSINE
Perifosine, also known as KRX-0401, is a synthetic novel alkylphospholipid (ALP) and a potent antitumor agents which inhibits PH domain mediated AKT membrane recruitment and activation. Perifosine structure has been elucidated through X-ray crystallography and it shows the similar structure with phospholipids that are the main constituents of cellular membranes. Perifosine is soluble in water and ethanol with solubility of 14 mg/mL and 92 mg/mL, respectively. But Perifosine solubility in DMSO is poor. Commercially researchers can obtain Perifosine with the price of about $210/mg from suppliers selleck chemicals. Perifosine stability keeps good for at least 2 years for the dry solid when stored at -20°C and for 6 months at -80°C in DMSO.

IN VITRO ACTIVITY
Kinase assay indicates that Perifosine (KRX-0401) produce the potent inhibitory activity against Akt with IC50 of 4.7 µM. In multiple myeloma (MM) cells, baseline phosphorylation of Akt is also completely inhibited by Perifosine treatment in a time- and dose-dependent mode. From MTT assays, Perifosine significantly inhibits growth of MM cell lines at 48 hours with IC50 ranging from 1 μM to 12.5 μM. The cytotoxicity of perifosine is also assessed in tumor cells from MM patients. Furthermore, Perifosine treatment results in the induction of JNK/caspase-dependent MM cell apoptosis by inducing phosphorylation of JNK, since JNK inhibitor SP600125 markedly inhibits perifosine-induced phosphorylation of JNK and caspase-8 cleavage. [2] In solid tumor therapy, Perifosine also show great effects. In HepG2 and Bel-7402 human hepatocellular carcinoma cells, Perifosine inhibits the cell growth in a dose-dependent manner, arrests cell cycle progression at the G(2) phase, and produces proapoptotic effect. [3] Combination treatment of perifosine and other drugs is also constructed. For example, inhibition of ERK signaling by U0126 synergistically enhances the cytotoxicity triggered by perifosine in MM cell lines. Besides, Perifosine also enhances cytotoxicity of conventional agents including doxorubicin and melphalan. [2]

IN VIVO ACTIVITY
In vivo, Perifosine also produces the inhibitory effect on cancer cell growth. In mice infected with MM.1S MM cells, oral administration of perifosine significantly reduces MM tumor growth and increased survival compared with control animals. [2] In addition, Perifosine also induces marrow hypercellularity and splenic white pulp expansion. Coupled with its in vitro MM cytotoxicity, Perifosine is considered as the candidate for clinical trials for patients with MM. [4] Combination study on perifosine and other drugs gains much progress. Animal studies suggest that perifosine and temozolomide combination therapy produces more effective results than temozolomide treatment alone. [5] Both in vitro and in vivo results provides the possibility for clinical application of Perifosine.

REFERENCES
[1] Vyomesh Patel, et al. Perifosine, a novel alkylphospholipid, induces p21(WAF1) expression in squamous carcinoma cells through a p53-independent pathway, leading to loss in cyclin-dependent kinase activity and cell cycle arrest. Cancer Res, 2002, 62(5), 1401-1409.
[2] Hideshima T, 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.
[3] Fei HR, et al. Perifosine induces cell cycle arrest and apoptosis in human hepatocellular carcinoma cell lines by blockade of Akt phosphorylation. Cytotechnology, 2010, 62(5), 449-460.
[4] Catley L, et al. Alkyl phospholipid perifosine induces myeloid hyperplasia in a murine myeloma model. Exp Hematol, 2007, 32(7), 1038-1046.
[5] Momota H, et al. Perifosine inhibits multiple signaling pathways in glial progenitors and cooperates with temozolomide to arrest cell proliferation in gliomas in vivo. Cancer Res, 2005, 65(16), 7429-7435.

Cat.No.	Product Name	Information
S1037	Perifosine	Perifosine is a novel Akt inhibitor with IC50 of 4.7 μM in MM.1S cells, targets pleckstrin homology domain of Akt. Phase 3.
S1460	SP600125	SP600125 (Nsc75890) is a broad-spectrum JNK inhibitor for JNK1, JNK2 and JNK3 with IC50 of 40 nM, 40 nM and 90 nM in cell-free assays, respectively; 10-fold greater selectivity against MKK4, 25-fold greater selectivity against MKK3, MKK6, PKB, and PKCα, and 100-fold selectivity against ERK2, p38, Chk1, EGFR etc. SP600125 is also a broad‐spectrum inhibitor of serine/threonine kinases including Aurora kinase A，FLT3 and TRKA with of IC50 of 60 nM, 90 nM and 70 nM. SP600125 inhibits autophagy and activates apoptosis.
S1102	U0126-EtOH	U0126-EtOH is a highly selective inhibitor of MEK1/2 with IC50 of 0.07 μM/0.06 μM in cell-free assays, 100-fold higher affinity for ΔN3-S218E/S222D MEK than PD98059. U0126 inhibits autophagy and mitophagy with antiviral activity.
S1208	Doxorubicin (DOX) HCl	Doxorubicin (DOX) HCl is an antibiotic agent that inhibits human DNA topoisomerase I and topoisomerase II with IC50s of 0.8 μM and 2.67 μM, respectively. Doxorubicin reduces basal phosphorylation of AMPK. Doxorubicin is used in the concomitant treatment of HIV-infected patients but is found to be at high risk of HBV reactivation.This product may precipitate when dissolved in PBS solution. It is recommended to prepare the stock solution in pure water and dilute with either pure water or saline to obtain the working solution.Doxorubicin (Adriamycin) HCl can be used to induce animal models of kidney disease.
S1237	TMZ(Temozolomide)	TMZ(Temozolomide) is a monofunctional SN-1 alkylating agent that can modify nitrogen atoms in the DNA ring and the extracyclic oxygen group, chemically converted to MTIC and degrades to methyldiazonium cation, which transfers methyl groups to DNA at physiologic pH. A DNA damage inducer in L-1210 and L-1210/BCNU cells. Temozolomide induces apoptosis and exhibits antitumor activity.