This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kondapaka, S. B. Articles by Roy, K. K. Search for Related Content PubMed PubMed Citation Articles by Kondapaka, S. B. Articles by Roy, K. K.

Clinical Trials Unit, Developmental Therapeutics Program, National Cancer Institute, Bethesda, MD

Requests for Reprints:Krishnendu K. Roy, National Institutes of Health, 10 Center Drive, Building 10, Room 6N 113, Bethesda, MD 20892-5680. Phone: (301) 496-4119; Fax: (301) 480-7456. E-mail: kr91w{at}nih.gov

Perifosine is a novel p.o. bioavailable alkylphospholipid. Perifosine has displayed significant antiproliferative activity in vitro and in vivo in several human tumor model systems and has recently entered phase I clinical trials. Recent studies have identified that perifosine could cause cell cycle arrest with induction of p21^WAF1/CIP1 in a p53-independent fashion; however, the basis for that effect is not known. Structurally, perifosine resembles naturally occurring phospholipids. Therefore, we hypothesized that perifosine might perturb pathways related to phospholipids modulated by growth factor action. We demonstrate here that perifosine causes dose-dependent inhibition of protein kinase B/Akt phosphorylation and thus activation at concentrations causing growth inhibition of PC-3 prostate carcinoma cells. Only the myristoylated form of Akt (MYR-Akt), which bypasses the requirement for pleckstrin homology (PH) domain-mediated membrane recruitment, abrogated perifosine-mediated decrease of Akt phosphorylation and cell growth inhibition by perifosine. We demonstrate further that perifosine decreases the plasma membrane localization of Akt, and this is substantially relieved by MYR-Akt along with relief of downstream drug effect on induction of p21^WAF1/CIP1. Perifosine does not directly affect phosphoinositide 3-kinase (PI3K), phosphoinositide-dependent kinase 1, or Akt activity at concentrations inhibiting Akt phosphorylation and membrane localization. Our results demonstrate that Akt is an important cellular target of perifosine action. In addition, these studies show that the membrane translocation of certain PH domain-containing molecules can be greatly perturbed by the alkylphospholipid class of drugs and imply further that the PI3K/Akt pathway contributes to regulation of p21^WAF1/CIP1 expression.

Note:S. B. K. and S. S. S. equally contributed to this work.

Portions of this work were presented in abstract form in the Proc. Am. Assoc. Cancer Res., 43: Abs. 2977, 2002.

Received 5/27/03; revised 7/29/03; accepted 8/ 5/03.

This article has been cited by other articles:

				E. David, R. Sinha, J. Chen, S.-Y. Sun, J. L. Kaufman, and S. Lonial Perifosine Synergistically Enhances TRAIL-Induced Myeloma Cell Apoptosis via Up-Regulation of Death Receptors Clin. Cancer Res., August 15, 2008; 14(16): 5090 - 5098. [Abstract] [Full Text] [PDF]

				P. A Dennis Targeting Akt in Cancer: Promise, Progress, and Potential Pitfalls Am. Assoc. Cancer Res. Educ. Book, April 12, 2008; 2008(1): 25 - 35. [Abstract] [Full Text] [PDF]

				B. T. Hennessy, Y. Lu, E. Poradosu, Q. Yu, S. Yu, H. Hall, M. S. Carey, M. Ravoori, A. M. Gonzalez-Angulo, R. Birch, et al. Pharmacodynamic Markers of Perifosine Efficacy Clin. Cancer Res., December 15, 2007; 13(24): 7421 - 7431. [Abstract] [Full Text] [PDF]

				L. Toral-Barza, W.-G. Zhang, X. Huang, L. A. McDonald, E. J. Salaski, L. R. Barbieri, W.-D. Ding, G. Krishnamurthy, Y. B. Hu, J. Lucas, et al. Discovery of lactoquinomycin and related pyranonaphthoquinones as potent and allosteric inhibitors of AKT/PKB: mechanistic involvement of AKT catalytic activation loop cysteines Mol. Cancer Ther., November 1, 2007; 6(11): 3028 - 3038. [Abstract] [Full Text] [PDF]

				E. Tokuda, N. Fujita, T. Oh-hara, S. Sato, A. Kurata, R. Katayama, T. Itoh, T. Takenawa, K. Miyazono, and T. Tsuruo Casein Kinase 2 Interacting Protein-1, a Novel Akt Pleckstrin Homology Domain-Interacting Protein, Down-regulates PI3K/Akt Signaling and Suppresses Tumor Growth In vivo Cancer Res., October 15, 2007; 67(20): 9666 - 9676. [Abstract] [Full Text] [PDF]

				R. L. Vinall, K. Hwa, P. Ghosh, C.-X. Pan, P. N. Lara Jr., and R. W. de Vere White Combination Treatment of Prostate Cancer Cell Lines with Bioactive Soy Isoflavones and Perifosine Causes Increased Growth Arrest and/or Apoptosis Clin. Cancer Res., October 15, 2007; 13(20): 6204 - 6216. [Abstract] [Full Text] [PDF]

				A. H. van der Luit, S. R. Vink, J. B. Klarenbeek, D. Perrissoud, E. Solary, M. Verheij, and W. J. van Blitterswijk A new class of anticancer alkylphospholipids uses lipid rafts as membrane gateways to induce apoptosis in lymphoma cells Mol. Cancer Ther., August 1, 2007; 6(8): 2337 - 2345. [Abstract] [Full Text] [PDF]

				H. A. Elrod, Y.-D. Lin, P. Yue, X. Wang, S. Lonial, F. R. Khuri, and S.-Y. Sun The alkylphospholipid perifosine induces apoptosis of human lung cancer cells requiring inhibition of Akt and activation of the extrinsic apoptotic pathway Mol. Cancer Ther., July 1, 2007; 6(7): 2029 - 2038. [Abstract] [Full Text] [PDF]

				L. A. Fecher, S. D. Cummings, M. J. Keefe, and R. M. Alani Toward a Molecular Classification of Melanoma J. Clin. Oncol., April 20, 2007; 25(12): 1606 - 1620. [Abstract] [Full Text] [PDF]

				J. L. Arbiser, T. Kau, M. Konar, K. Narra, R. Ramchandran, S. A. Summers, C. J. Vlahos, K. Ye, B. N. Perry, W. Matter, et al. Solenopsin, the alkaloidal component of the fire ant (Solenopsis invicta), is a naturally occurring inhibitor of phosphatidylinositol-3-kinase signaling and angiogenesis Blood, January 15, 2007; 109(2): 560 - 565. [Abstract] [Full Text] [PDF]

				L. de la Pena, W. E. Burgan, D. J. Carter, M. G. Hollingshead, M. Satyamitra, K. Camphausen, and P. J. Tofilon Inhibition of Akt by the alkylphospholipid perifosine does not enhance the radiosensitivity of human glioma cells. Mol. Cancer Ther., June 1, 2006; 5(6): 1504 - 1510. [Abstract] [Full Text] [PDF]

				M. Nyakern, A. Cappellini, I. Mantovani, and A. M. Martelli 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., June 1, 2006; 5(6): 1559 - 1570. [Abstract] [Full Text] [PDF]

				G. Powis, N. Ihle, and D. L. Kirkpatrick Practicalities of drugging the phosphatidylinositol-3-kinase/akt cell survival signaling pathway. Clin. Cancer Res., May 15, 2006; 12(10): 2964 - 2966. [Full Text] [PDF]

				T. Hideshima, L. Catley, H. Yasui, K. Ishitsuka, N. Raje, C. Mitsiades, K. Podar, N. C. Munshi, D. Chauhan, P. G. Richardson, et al. Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells Blood, May 15, 2006; 107(10): 4053 - 4062. [Abstract] [Full Text] [PDF]

				J. J. Gills, S. Holbeck, M. Hollingshead, S. M. Hewitt, A. P. Kozikowski, and P. A. Dennis Spectrum of activity and molecular correlates of response to phosphatidylinositol ether lipid analogues, novel lipid-based inhibitors of Akt. Mol. Cancer Ther., March 1, 2006; 5(3): 713 - 722. [Abstract] [Full Text] [PDF]

				S. R. Vink, S. Lagerwerf, E. Mesman, J. H.M. Schellens, A. C. Begg, W. J. van Blitterswijk, and M. Verheij Radiosensitization of Squamous Cell Carcinoma by the Alkylphospholipid Perifosine in Cell Culture and Xenografts Clin. Cancer Res., March 1, 2006; 12(5): 1615 - 1622. [Abstract] [Full Text] [PDF]

				C. A. Granville, R. M. Memmott, J. J. Gills, and P. A. Dennis Handicapping the Race to Develop Inhibitors of the Phosphoinositide 3-Kinase/Akt/Mammalian Target of Rapamycin Pathway Clin. Cancer Res., February 1, 2006; 12(3): 679 - 689. [Abstract] [Full Text] [PDF]

				P. Wlodarski, M. Kasprzycka, X. Liu, M. Marzec, E. S. Robertson, A. Slupianek, and M. A. Wasik Activation of Mammalian Target of Rapamycin in Transformed B Lymphocytes Is Nutrient Dependent but Independent of Akt, Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase, Insulin Growth Factor-I, and Serum Cancer Res., September 1, 2005; 65(17): 7800 - 7808. [Abstract] [Full Text] [PDF]

				H. Momota, E. Nerio, and E. C. Holland Perifosine Inhibits Multiple Signaling Pathways in Glial Progenitors and Cooperates With Temozolomide to Arrest Cell Proliferation in Gliomas In vivo Cancer Res., August 15, 2005; 65(16): 7429 - 7435. [Abstract] [Full Text] [PDF]

				K. K. Hoyer, M. Herling, K. Bagrintseva, D. W. Dawson, S. W. French, M. Renard, J. G. Weinger, D. Jones, and M. A. Teitell T Cell Leukemia-1 Modulates TCR Signal Strength and IFN-{gamma} Levels through Phosphatidylinositol 3-Kinase and Protein Kinase C Pathway Activation J. Immunol., July 15, 2005; 175(2): 864 - 873. [Abstract] [Full Text] [PDF]

				M. Rahmani, E. Reese, Y. Dai, C. Bauer, S. G. Payne, P. Dent, S. Spiegel, and S. Grant 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 Cancer Res., March 15, 2005; 65(6): 2422 - 2432. [Abstract] [Full Text] [PDF]

				R. W. Caron, A. Yacoub, M. Li, X. Zhu, C. Mitchell, Y. Hong, W. Hawkins, T. Sasazuki, S. Shirasawa, A. P. Kozikowski, et al. Activated forms of H-RAS and K-RAS differentially regulate membrane association of PI3K, PDK-1, and AKT and the effect of therapeutic kinase inhibitors on cell survival Mol. Cancer Ther., February 1, 2005; 4(2): 257 - 270. [Abstract] [Full Text] [PDF]

				L. Van Ummersen, K. Binger, J. Volkman, R. Marnocha, K. Tutsch, J. Kolesar, R. Arzoomanian, D. Alberti, and G. Wilding A Phase I Trial of Perifosine (NSC 639966) on a Loading Dose/Maintenance Dose Schedule in Patients with Advanced Cancer Clin. Cancer Res., November 15, 2004; 10(22): 7450 - 7456. [Abstract] [Full Text] [PDF]

				G. P. Dasmahapatra, P. Didolkar, M. C. Alley, S. Ghosh, E. A. Sausville, and K. K. Roy In vitro Combination Treatment with Perifosine and UCN-01 Demonstrates Synergism against Prostate (PC-3) and Lung (A549) Epithelial Adenocarcinoma Cell Lines Clin. Cancer Res., August 1, 2004; 10(15): 5242 - 5252. [Abstract] [Full Text] [PDF]