Summary
The effect of the single-chain alkylphospholipid perifosine was analyzed in p53wild-type (SKW6.4, OCI and MOLM), p53mutated (BJAB, MAVER) and p53null (HL-60) leukemic cell lines. Perifosine promoted cytotoxicity with a combination of apoptosis induction in all cell lines and cell cycle block at the G2M checkpoint, which was selectively observed in p53mutated BJAB and MAVER cell lines. At the molecular level, perifosine induced hypophosphorylation of retinoblastoma protein and the degradation of E2F1 protein in p53mutated but not in p53wild-type cells. These data indicate that perifosine potentially represents an innovative therapeutic approach for p53mutated hematological malignancies.
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References
van Blitterswijk WJ, Verheij M (2008) Anticancer alkylphospholipids: mechanisms of action, cellular sensitivity and resistance, and clinical prospects. Curr Pharm Des 14:2061–2074
Nyakern M, Cappellini A, Mantovani I, Martelli AM (2006) Synergistic induction of apoptosis in human leukemia T cells by the Akt inhibitor perifosine and etoposide through activation of intrinsic and Fas-mediated extrinsic cell death pathways. Mol Cancer Ther 5:1559–1570
Tazzari PL, Tabellini G, Ricci F et al (2008) Synergistic proapoptotic activity of recombinant TRAIL plus the Akt inhibitor perifosine in acute myelogenous leukemia cells. Cancer Res 68:9394–9403
Mitani N, Niwa Y, Okamoto Y (2007) Surveyor nuclease-based detection of p53 gene mutations in haematological malignancy. Ann Clin Biochem 44:557–559
Secchiero P, Zerbinati C et al (2007) Synergistic cytotoxic activity of recombinant TRAIL plus the non-genotoxic activator of the p53 pathway nutlin-3 in acute myeloid leukemia cells. Curr Drug Metab 8:395–403
Milani D, Zauli G, Rimondi E et al (2003) Tumour necrosis factor-related apoptosis-inducing ligand sequentially activates pro-survival and pro-apoptotic pathways in SK-N-MC neuronal cells. J Neurochem 86:126–135
Secchiero P, Zerbinati C, Rimondi E et al (2004) TRAIL promotes the survival, migration and proliferation of vascular smooth muscle cells. Cell Mol Life Sci 61:1965–1974
Zauli G, Visani G, Bassini A et al (1996) Nuclear translocation of protein kinase C-α and -ζ isoforms in HL-60 cells induced to differentiate along the granulocytic lineage by all-trans retinoic acid (ATRA). Br J Haematol 93:542–550
Chen HZ, Tsai SY, Leone G (2009) Emerging roles of E2Fs in cancer: an exit from cell cycle control. Nat Rev Cancer 9:785–797
Acknowledgments
This study was supported by AIRC (to GZ) and Linfonet (to CC and VG) projects.
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Celeghini, C., Voltan, R., Rimondi, E. et al. Perifosine selectively induces cell cycle block and modulates retinoblastoma and E2F1 protein levels in p53 mutated leukemic cell lines. Invest New Drugs 29, 392–395 (2011). https://doi.org/10.1007/s10637-009-9370-1
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DOI: https://doi.org/10.1007/s10637-009-9370-1