Disease relevance of NSC639966

• Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts [1].
• Finally, perifosine demonstrates significant antitumor activity in a human plasmacytoma mouse model, associated with down-regulation of Akt phosphorylation in tumor cells [2].
• However, the efficacy of perifosine in human gliomas has not been established [3].
• In this study, we investigated the effect of perifosine, a p.o.-bioavailable ALK, on the cell cycle kinetics of immortalized keratinocytes (HaCaT) as well as head and neck squamous carcinoma cells [4].
• As Akt is activated in approximately 70% of human glioblastomas, we investigated the impact of perifosine on glia in culture and on a mouse glioma model in vivo [3].

High impact information on NSC639966

• We have found that synthetic alkyl-lysophospholipids (ALPs) edelfosine and perifosine induced apoptosis in MM cell lines and patient MM cells, whereas normal B and T lymphocytes were spared [1].
• Interestingly, phosphorylation of extracellular signal-related kinase (ERK) is increased by perifosine; conversely, MEK inhibitor synergistically enhances Perifosine-induced cytotoxicity in MM cells [2].
• Inhibition of JNK abrogates perifosine-induced cytotoxicity, suggesting that JNK plays an essential role in perifosine-induced apoptosis [2].
• Neither exogenous interleukin-6 (IL-6) nor insulinlike growth factor 1 (IGF-1) overcomes Perifosine-induced cytotoxicity [2].
• Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells [2].

Chemical compound and disease context of NSC639966

• With these results, we combined perifosine and temozolomide as treatment of platelet-derived growth factor B-driven gliomas in mice [3].
• We performed a phase I trial with an analogue of miltefosine, perifosine (D-21266), which was expected to induce less gastrointestinal toxicity [5].

Biological context of NSC639966

• Importantly, Perifosine induces apoptosis even of MM cells adherent to bone marrow stromal cells [2].
• The minimal p21 promoter region required for perifosine-induced p21 promoter activation contains four consensus Sp1-binding sites [6].
• We observed that perifosine induces the accumulation of p21(waf1/cip1) mRNA without affecting p21(waf1/cip1) mRNA stability [6].
• A 72-h exposure of the MDA468 and PC3 cells to perifosine alone resulted in cell death in a dose-dependent manner, which was enhanced by cetuximab [7].
• CONCLUSIONS: As the concentrations of UCN-01 and perifosine causing synergistic inhibition of cell growth are clinically achievable without prominent toxicity, these data support the development of clinical studies with this combination [8].

Anatomical context of NSC639966

• Perifosine induces significant cytotoxicity in both MM cell lines and patient MM cells resistant to conventional therapeutic agents [2].
• Perifosine is a synthetic novel alkylphospholipid, a new class of antitumor agents which targets cell membranes and inhibits Akt activation [2].
• Perifosine is an oral Akt inhibitor which exerts a marked cytotoxic effect on human tumor cell lines, and is currently being tested in several phase II trials for treatment of major human cancers [3].
• In vitro, KB cells showed a remarkably high uptake and sensitivity for perifosine compared with A431 and HNXOE cells [9].

Associations of NSC639966 with other chemical compounds

• Coadministration of histone deacetylase inhibitors and perifosine synergistically induces apoptosis in human leukemia cells through Akt and ERK1/2 inactivation and the generation of ceramide and reactive oxygen species [10].

Gene context of NSC639966

• 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 [4].
• Analysis of cdk complexes in vitro demonstrated that perifosine, up to 20 microM, did not directly interfere with these enzymes [4].
• However, inhibition of JNK activation (e.g., by the JNK inhibitor SP600125) did not attenuate sodium butyrate/perifosine-induced apoptosis [10].
• Enhancement of antitumor activity of the anti-EGF receptor monoclonal antibody cetuximab/C225 by perifosine in PTEN-deficient cancer cells [7].
• These results indicate that perifosine is an effective drug in gliomas in which Akt and Ras-Erk 1/2 pathways are frequently activated, and may be a new candidate for glioma treatment in the clinic [3].

Analytical, diagnostic and therapeutic context of NSC639966

• Taken together, our data provide the rationale for clinical trials of perifosine to improve patient outcome in MM [2].
• Radiosensitization of squamous cell carcinoma by the alkylphospholipid perifosine in cell culture and xenografts [11].
• In vivo, the response of human KB squamous cell carcinoma xenografts was measured after treatment with perifosine, irradiation, and the combination [11].
• Comparable tumor accumulation was observed for A431 and HNXOE tumors, whereas perifosine uptake by KB xenografts was substantially higher [9].
• Phase I and pharmacological study of daily oral administration of perifosine (D-21266) in patients with advanced solid tumours [5].

References