Perifosine, a Novel Alkylphospholipid, Induces p21WAF1 Expression in Squamous Carcinoma Cells through a p53-independent Pathway, Leading to Loss in Cyclin-dependent Kinase Activity and Cell Cycle Arrest

作者: Edward A. Sausville , Adrian M. Senderowicz , J. Sivio Gutkind , Vyomesh Patel , Tyler Lahusen

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摘要: Alkylphospholipids (ALKs) are a novel class of antineoplastic compounds that display potent antiproliferative activity against several in vitro and vivo human tumor models. However, the mechanism by which these agents exert this desired effect is still unclear. In study, we investigated perifosine, p.o.-bioavailable ALK, on cell cycle kinetics immortalized keratinocytes (HaCaT) as well head neck squamous carcinoma cells. All cells were sensitive to properties perifosine with an IC(50) similar0.6-8.9 microM. Cell arrest at G(1)-S G(2)-M boundaries was observed HN12, HN30, HaCaT independent p53 function, preceded loss cdc2 cyclin-dependent kinase (cdk) 2 activity. Analysis cdk complexes demonstrated up 20 microM, did not directly interfere enzymes. aphidicolin-synchronized HN12 released presence (10 microM) increased expression total p21(WAF1) association cyclin-cdk resulting reduced HCT116 isogenic lines used assess role induction perifosine. This compound (20 induced both arrest, together wild-type p53(-/-) clones. By contrast, p21(-/-) variants no or arrest. Similar results obtained other ALK congeners (miltefosine edelfosine). These data, therefore, indicate blocks progression inducing p21(WAF1), irrespective may be exploited clinically because majority malignancies harbor mutations.

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