tcsc0209 Perifosine

Perifosine is an oral Akt inhibitor. All cells are sensitive to the antiproliferative properties of Perifosine with an IC₅₀ of ~0.6-8.9 μM.

IC50 & Target: Akt^[1]

In Vitro: The IC₅₀ for growth of Ntv-a/LacZ cell lines is determined by MTT assay. When the cells are cultured for 48 hours in 10% FCS-supplemented media, the IC₅₀ for cells with constitutively active PDGF, Ras, or Akt signaling is similar and found to be ~45 μM^[1].Perifosine, a oral-bioavailable alkylphospholipid (ALK), on the cell cycle kinetics of immortalized keratinocytes (HaCaT) as well as head and neck squamous carcinoma cells. Proliferation is assessed by the incorporation of [³H]thymidine into cellular DNA. Exposure to Perifosine (0.1-30 μM) for 24 h results in a dose-dependent inhibition of [³H]thymidine uptake in all cell lines tested. The IC₅₀s for growth are between 0.6 and 8.9 μM, reaching IC₈₀s of ~10 μM. Perifosine blocks cell cycle progression of head and neck squamous carcinoma cells at G₁-S and G₂-M by inducing p21^WAF1, irrespective of p53 function, and may be exploited clinically because the majority of human malignancies harbor p53 mutations. Perifosine (20 μM) induces both G₁-S and G₂-M cell cycle arrest, together with p21^WAF1 expression in both p53 wild-type and p53^-/- clones^[2].

In Vivo: Mice are identified with tumors by bioluminescence imaging and either treated them with 100 mg/kg Temozolomide, or 30 mg/kg Perifosine, or a combination with 100 mg/kg Temozolomide and 30 mg/kg Perifosine (Temozolomide+Perifosine) for 3 to 5 days. The mice are sacrificed and tumors analyzed histologically for cell proliferation by Ki-67 immunostaining. Ki-67 staining index is significantly reduced in mice treated with either Temozolomide (Ki-67 staining index=5.5±1.2%, n=4, P=0.0019) or Perifosine (Ki-67 staining index=3.2±1.1%, n=3, P=0.001) compared with Control, demonstrating the inhibitory effect on proliferation. Most importantly, the tumors treated with Temozolomide+Perifosine have the lowest Ki-67 staining index (1.7±1.2%, n=3, P=0.0005). The additional treatment with Perifosine results in a significantly lower proliferation rate than Temozolomide alone (P=0.0087)^[1]. Perifosine markedly decreases p-Akt from 10 min to 24 hours and subsequently, moderately decreased p-S6 from 1h to 24 h after injection^[3].