Perifosine-a new option in treatment of acute myeloid leukemia?

Expert Opinion on Investigational Drugs

Volumn 22, Issue 10, 2013, Pages 1315-1327

  Krawczyk, Janusz ^a   Keane, Niamh ^b   Swords, Ronan ^c   O'Dwyer, Michael ^b   Freeman, Ciara L ^d   Giles, Francis J ^b  

^a UNIVERSITY HOSPITAL GALWAY   (Ireland)

^b NATIONAL UNIVERSITY OF IRELAND   (Ireland)

^c UNIVERSITY OF MIAMI   (United States)

^d BARTS HEALTH NHS TRUST   (United Kingdom)

Author keywords

Acute myeloid leukemia; Chronic lymphocytic; Leukemia; Perifosine; PI3K AKT pathway; Targeted molecular therapy

Indexed keywords

BORTEZOMIB; CAPECITABINE; MILTEFOSINE; PERIFOSINE; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; PROTEIN KINASE C; SORAFENIB;

ACUTE GRANULOCYTIC LEUKEMIA; ADVERSE OUTCOME; ANEMIA; ANOREXIA; ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER CELL; CANCER RECURRENCE; CHRONIC MYELOID LEUKEMIA; CYTOPENIA; DIARRHEA; DRUG DOSE REDUCTION; DRUG EFFICACY; DRUG SAFETY; DRUG STRUCTURE; DRUG WITHDRAWAL; ENZYME ACTIVATION; FATIGUE; GASTROINTESTINAL TOXICITY; HODGKIN DISEASE; HUMAN; IN VITRO STUDY; IN VIVO STUDY; LARGE CELL LYMPHOMA; LYMPHATIC LEUKEMIA; LYMPHOCYTOMA; METASTATIC COLORECTAL CANCER; MUCOSA INFLAMMATION; MULTIPLE MYELOMA; MUSCULOSKELETAL PAIN; MYELODYSPLASTIC SYNDROME; MYELOID LEUKEMIA; NAUSEA; NEUTROPENIA; NONHUMAN; PNEUMONIA; PROTEIN STRUCTURE; PROTEIN SYNTHESIS; SIGNAL TRANSDUCTION; SKIN MANIFESTATION; SOLID TUMOR; THROMBOCYTOPENIA; UNSPECIFIED SIDE EFFECT;

ANTINEOPLASTIC AGENTS; CLINICAL TRIALS AS TOPIC; HUMANS; LEUKEMIA, MYELOID, ACUTE; MOLECULAR STRUCTURE; MOLECULAR TARGETED THERAPY; PHOSPHORYLCHOLINE; PROTO-ONCOGENE PROTEINS C-AKT; SIGNAL TRANSDUCTION; TREATMENT OUTCOME;

EID: 84884261429     PISSN: 13543784     EISSN: 17447658     Source Type: Journal    
DOI: 10.1517/13543784.2013.826648     Document Type: Article

References (100)

1. National cancer Institue. Seer stat fact sheets: Acute myeloid leukemia. Available from: http://seercancergov/statfacts/html/amylhtml [Accessed 14 February 2013]
2. Haferlach T. Molecular genetic pathways as therapeutic targets in acute myeloid leukemia. Hematol Am Soc Hematol Educ Program 2008;400-11
3. Brennan P, Mehl AM, Jones M, et al. Phosphatidylinositol 3-kinase is essential for the proliferation of lymphoblastoid cells. Oncogene 2002;21(8):1263-71
4. Yuan TL, Cantley LC. Pi3k pathway alterations in cancer: variations on a theme. Oncogene 2008;27(41):5497-510
5. Pardee AB. Tumor progression-targets for differential therapy. J Cell Physiol 2006;209(3):589-91
6. Sugimoto Y, Whitman M, Cantley LC, et al. Evidence that the rous sarcoma virus transforming gene product phosphorylates phosphatidylinositol and diacylglycerol. Proc Natl Acad Sci USA 1984;81(7):2117-21
7. Leevers SJ, Vanhaesebroeck B, Waterfield MD. Signalling through phosphoinositide 3-kinases: the lipids take centre stage. Curr Opin Cell Biol 1999;11(2):219-25
8. Vanhaesebroeck B, Leevers SJ, Panayotou G, et al. Phosphoinositide 3-kinases: a conserved family of signal transducers. Trends Biochem Sci 1997;22(7):267-72
9. Giordanetto F, Wallberg A, Cassel J, et al. Discovery of 4-morpholinopyrimidin-6-one and 4-morpholinopyrimidin-2-one-containing phosphoinositide 3-kinase (pi3k) p110beta isoform inhibitors through structure-based fragment optimisation. Bioorg Med Chem Lett 2012;22(21):6665-70
10. Domin J, Gaidarov I, Smith ME, et al. The class ii phosphoinositide 3-kinase pi3k-c2alpha is concentrated in the trans-golgi network and present in clathrin-coated vesicles. The J Biol Chem 2000;275(16):11943-50
11. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 2006;7(8):606-19
12. Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase akt pathway in human cancer. Nat Rev Cancer 2002;2(7):489-501
13. Carpenter CL, Duckworth BC, Auger KR, et al. Purification and characterization of phosphoinositide 3-kinase from rat liver. J biol Chem 1990;265(32):19704-11
14. Martelli AM, Evangelisti C, Chiarini F, et al. Targeting the pi3k/akt/mtor signaling network in acute myelogenous leukemia. Expert Opin Investig Drugs 2009;18(9):1333-49
15. Chan TO, Rittenhouse SE, Tsichlis PN. Akt/pkb and other d3 phosphoinositide-regulated kinases: Kinase activation by phosphoinositide- dependent phosphorylation. Ann Rev Biochem 1999;68:965-1014
16. Ellenbroek SI, Collard JG. Rho gtpases: functions and association with cancer. Clin Exp Metastasis 2007;24(8):657-72
17. Chung J, Kuo CJ, Crabtree GR, et al. Rapamycin-fkbp specifically blocks growth-dependent activation of and signaling by the 70 kd s6 protein kinases. Cell 1992;69(7):1227-36
18. Yamasaki T, Takahashi A, Pan J, et al. Phosphorylation of activation transcription factor-2 at serine 121 by protein kinase c controls c-jun-mediated activation of transcription. J Biol Chem 2009;284(13):8567-81
19. Datta SR, Dudek H, Tao X, et al. Akt phosphorylation of bad couples survival signals to the cell-intrinsic death machinery. Cell 1997;91(2):231-41
20. Zhao S, Konopleva M, Cabreira-Hansen M, et al. Inhibition of phosphatidylinositol 3-kinase dephosphorylates bad and promotes apoptosis in myeloid leukemias. Leukemia 2004;18(2):267-75
21. Hay N. The akt-mtor tango and its relevance to cancer. Cancer Cell 2005;8(3):179-83
22. Fu L, Kim YA, Wang X, et al. Perifosine inhibits mammalian target of rapamycin signaling through facilitating degradation of major components in the mtor axis and induces autophagy. Cancer Res 2009;69(23):8967-76
23. Gingras AC, Kennedy SG, O'Leary MA, et al. 4e-bp1, a repressor of mrna translation, is phosphorylated and inactivated by the akt(pkb) signaling pathway. Genes Dev 1998;12(4):502-13
24. Hara K, Yonezawa K, Weng QP, et al. Amino acid sufficiency and mtor regulate p70 s6 kinase and eif-4e bp1 through a common effector mechanism. J Biol Chem 1998;273(23):14484-94
25. McLeod LE, Proud CG. Atp depletion increases phosphorylation of elongation factor eef2 in adult cardiomyocytes independently of inhibition of mtor signalling. FEBS Lett 2002;531(3):448-52
26. Armengol G, Rojo F, Castellvi J, et al. 4e-binding protein 1: A key molecular "funnel factor" in human cancer with clinical implications. Cancer Res 2007;67(16):7551-5
27. Barlund M, Forozan F, Kononen J, et al. Detecting activation of ribosomal protein s6 kinase by complementary DNA and tissue microarray analysis. J Natl Cancer Inst 2000;92(15):1252-9
28. Nakamura JL, Garcia E, Pieper RO. S6k1 plays a key role in glial transformation. Cancer Res 2008;68(16):6516-23
29. Nyakern M, Cappellini A, Mantovani I, et al. 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 2006;5(6):1559-70
30. Brennan P, Babbage JW, Burgering BM, et al. Phosphatidylinositol 3-kinase couples the interleukin-2 receptor to the cell cycle regulator e2f. Immunity 1997;7(5):679-89
31. Chang F, Lee JT, Navolanic PM, et al. Involvement of pi3k/akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia 2003;17(3):590-603
32. Chappell WH, Steelman LS, Long JM, et al. Ras/raf/mek/erk and pi3k/pten/akt/mtor inhibitors: rationale and importance to inhibiting these pathways in human health. Oncotarget 2011;2(3):135-64
33. Murga C, Laguinge L, Wetzker R, et al. Activation of akt/protein kinase b by g protein-coupled receptors. A role for alpha and beta gamma subunits of heterotrimeric g proteins acting through phosphatidylinositol-3-oh kinasegamma. J Biol Chem 1998;273(30):19080-5
34. Koch A, Mancini A, El Bounkari O, et al. The sh2-domian-containing inositol 5-phosphatase (ship)-2 binds to c-met directly via tyrosine residue 1356 and involves hepatocyte growth factor (hgf)-induced lamellipodium formation, cell scattering and cell spreading. Oncogene 2005;24(21):3436-47
35. Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002;296(5573):1655-7
36. Chaurio RA, Janko C, Munoz LE, et al. Phospholipids: key players in apoptosis and immune regulation. Molecules 2009;14(12):4892-914
37. Pike LJ. The challenge of lipid rafts. J Lipid Res 2009;50(Suppl):S323-8
38. Pike LJ. Rafts defined: a report on the keystone symposium on lipid rafts and cell function. J Lipid Res 2006;47(7):1597-8
39. Gao X, Zhang J. Spatiotemporal analysis of differential akt regulation in plasma membrane microdomains. Mol Biol Cell 2008;19(10):4366-73
40. Cully M, You H, Levine AJ, et al. Beyond pten mutations: the pi3k pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer 2006;6(3):184-92
41. McCubrey JA, Steelman LS, Chappell WH, et al. Mutations and deregulation of ras/raf/mek/erk and pi3k/pten/akt/mtor cascades which alter therapy response. Oncotarget 2012;3(9):954-87
42. Taylor V, Wong M, Brandts C, et al. 5C phospholipid phosphatase ship-2 causes protein kinase b inactivation and cell cycle arrest in glioblastoma cells. Mol Cell Biol 2000;20(18):6860-71
43. Luo JM, Yoshida H, Komura S, et al. Possible dominant-negative mutation of the ship gene in acute myeloid leukemia. Leukemia 2003;17(1):1-8
44. West KA, Castillo SS, Dennis PA. Activation of the pi3k/akt pathway and chemotherapeutic resistance. Drug Resist Updat 2002;5(6):234-48
45. Plo I, Bettaieb A, Payrastre B, et al. The phosphoinositide 3-kinase/akt pathway is activated by daunorubicin in human acute myeloid leukemia cell lines. FEBS Lett 1999;452(3):150-4
46. Tamburini J, Elie C, Bardet V, et al. Constitutive phosphoinositide 3-kinase/akt activation represents a favorable prognostic factor in de novo acute myelogenous leukemia patients. Blood 2007;110(3):1025-8
47. Billottet C, Grandage VL, Gale RE, et al. A selective inhibitor of the p110delta isoform of pi 3-kinase inhibits aml cell proliferation and survival and increases the cytotoxic effects of vp16. Oncogene 2006;25(50):6648-59
48. Polak R, Buitenhuis M. The pi3k/pkb signaling module as key regulator of hematopoiesis: implications for therapeutic strategies in leukemia. Blood 2012;119(4):911-23
49. Sujobert P, Bardet V, Cornillet-Lefebvre P, et al. Essential role for the p110delta isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia. Blood 2005;106(3):1063-6
50. Xu Q, Simpson SE, Scialla TJ, et al. Survival of acute myeloid leukemia cells requires pi3 kinase activation. Blood 2003;102(3):972-80
51. Birkenkamp KU, Geugien M, Schepers H, et al. Constitutive nf-kappab DNA-binding activity in aml is frequently mediated by a ras/pi3-k/pkbdependent pathway. Leukemia 2004;18(1):103-12
52. Steelman LS, Pohnert SC, Shelton JG, et al. Jak/stat, raf/mek/erk, pi3k/akt and bcr-abl in cell cycle progression and leukemogenesis. Leukemia 2004;18(2):189-218
53. Minami Y, Yamamoto K, Kiyoi H, et al. Different antiapoptotic pathways between wild-type and mutated flt3: insights into therapeutic targets in leukemia. Blood 2003;102(8):2969-75
54. Kindler T, Lipka DB, Fischer T. Flt3 as a therapeutic target in aml: still challenging after all these years. Blood 2010;116(24):5089-102
55. Beghini A, Bellini M, Magnani I, et al. Sti 571 inhibition effect on kitasn822lys-mediated signal transduction cascade. Exp Hematol 2005;33(6):682-8
56. Choudhary C, Schwable J, Brandts C, et al. Aml-associated flt3 kinase domain mutations show signal transduction differences compared with flt3 itd mutations. Blood 2005;106(1):265-73
57. Larizza L, Magnani I, Beghini A. The kasumi-1 cell line: a t(8;21)-kit mutant model for acute myeloid leukemia. Leuk Lymphoma 2005;46(2):247-55
58. Cheong JW, Eom JI, Maeng HY, et al. Phosphatase and tensin homologue phosphorylation in the c-terminal regulatory domain is frequently observed in acute myeloid leukaemia and associated with poor clinical outcome. Br J Haematol 2003;122(3):454-6
59. Guthridge MA, Stomski FC, Thomas D, et al. Mechanism of activation of the gm-csf, il-3, and il-5 family of receptors. Stem Cells 1998;16(5):301-13
60. Brandts CH, Sargin B, Rode M, et al. Constitutive activation of akt by flt3 internal tandem duplications is necessary for increased survival, proliferation, and myeloid transformation. Cancer Res 2005;65(21):9643-50
61. Min YH, Eom JI, Cheong JW, et al. Constitutive phosphorylation of akt/pkb protein in acute myeloid leukemia: its significance as a prognostic variable. Leukemia 2003;17(5):995-7
62. O'Gorman DM, McKenna SL, McGahon AJ, et al. Sensitisation of hl60 human leukaemic cells to cytotoxic drug-induced apoptosis by inhibition of pi3-kinase survival signals. Leukemia 2000;14(4):602-11
63. Grandage VL, Gale RE, Linch DC, et al. Pi3-kinase/akt is constitutively active in primary acute myeloid leukaemia cells and regulates survival and chemoresistance via nf-kappab, mapkinase and p53 pathways. Leukemia 2005;19(4):586-94
64. Bortul R, Tazzari PL, Billi AM, et al. Deguelin, a pi3k/akt inhibitor, enhances chemosensitivity of leukaemia cells with an active pi3k/akt pathway. Br J Haematol 2005;129(5):677-86
65. Barragan M, Bellosillo B, Campas C, et al. Involvement of protein kinase c and phosphatidylinositol 3-kinase pathways in the survival of b-cell chronic lymphocytic leukemia cells. Blood 2002;99(8):2969-76
66. Ringshausen I, Schneller F, Bogner C, et al. Constitutively activated phosphatidylinositol-3 kinase (pi-3k) is involved in the defect of apoptosis in b-cll: association with protein kinase cdelta. Blood 2002;100(10):3741-8
67. de Frias M, Iglesias-Serret D, Cosialls AM, et al. Akt inhibitors induce apoptosis in chronic lymphocytic leukemia cells. Haematologica 2009;94(12):1698-707
68. Zhuang J, Hawkins SF, Glenn MA, et al. Akt is activated in chronic lymphocytic leukemia cells and delivers a pro-survival signal: the therapeutic potential of akt inhibition. Haematologica 2010;95(1):110-18
69. Mollinedo F, de la Iglesia-Vicente J, Gajate C, et al. In vitro and in vivo selective antitumor activity of edelfosine against mantle cell lymphoma and chronic lymphocytic leukemia involving lipid rafts. Clin Cancer Res 2010;16(7):2046-54
70. Kondapaka SB, Singh SS, Dasmahapatra GP, et al. Perifosine, a novel alkylphospholipid, inhibits protein kinase b activation. Mol Cancer Ther 2003;2(11):1093-103
71. Clive S, Gardiner J, Leonard RC. Miltefosine as a topical treatment for cutaneous metastases in breast carcinoma. Cancer Chemother Pharmacol 1999;44 Suppl:S29-30
72. Dorlo TP, Balasegaram M, Beijnen JH, et al. Miltefosine: a review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis. J Antimicrob Chemother 2012;67(11):2576-97
73. Fei HR, Chen G, Wang JM, et al. Perifosine induces cell cycle arrest and apoptosis in human hepatocellular carcinoma cell lines by blockade of akt phosphorylation. Cytotechnology 2010;62(5):449-60
74. Gills JJ, Dennis PA. Perifosine: update on a novel akt inhibitor. Curr Oncol Rep 2009;11(2):102-10
75. Pinton G, Manente AG, Angeli G, et al. Perifosine as a potential novel anti-cancer agent inhibits egfr/met-akt axis in malignant pleural mesothelioma. PLoS ONE 2012;7(5):e36856
76. Chiarini F, Del Sole M, Mongiorgi S, et al. The novel akt inhibitor, perifosine, induces caspase-dependent apoptosis and downregulates p-glycoprotein expression in multidrug-resistant human t-acute leukemia cells by a jnk-dependent mechanism. Leukemia 2008;22(6):1106-16
77. Tazzari PL, Tabellini G, Ricci F, et al. Synergistic proapoptotic activity of recombinant trail plus the akt inhibitor perifosine in acute myelogenous leukemia cells. Cancer Res 2008;68(22):9394-403
78. Vink SR, Lagerwerf S, Mesman E, et al. Radiosensitization of squamous cell carcinoma by the alkylphospholipid perifosine in cell culture and xenografts. Clin Cancer Res 2006;12(5):1615-22
79. Hideshima T, Catley L, Yasui H, et al. Perifosine, an oral bioactive novel alkylphospholipid, inhibits akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood 2006;107(10):4053-62
80. 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 2011;29(2):392-5
81. Papa V, Tazzari PL, Chiarini F, et al. Proapoptotic activity and chemosensitizing effect of the novel akt inhibitor perifosine in acute myelogenous leukemia cells. Leukemia 2008;22(1):147-60
82. Martelli AM, Papa V, Tazzari PL, et al. The novel akt inhibitor perifosine induces apoptosis, cell cycle arrest and synergizes with chemotherapeutic drugs in acute myelogenous leukemia cells by a JNK dependent mechanism -a novel therapeutic approach for leukemia displaying elevated akt signaling. ASH Annu Meet Abstr 2007;110(11):3355
83. Stommel JM, Kimmelman AC, Ying H, et al. Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 2007;318(5848):287-90
84. Dong S, Kang S, Gu TL, et al. 14-3-3 integrates prosurvival signals mediated by the akt and mapk pathways in znf198-fgfr1-transformed hematopoietic cells. Blood 2007;110(1):360-9
85. Rahmani M, Anderson A, Habibi JR, et al. The bh3-only protein bim plays a critical role in leukemia cell death triggered by concomitant inhibition of the pi3k/akt and mek/erk1/2 pathways. Blood 2009;114(20):4507-16
86. Rahmani M, Reese E, Dai Y, et al. 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 2005;65(6):2422-32
87. David E, Sinha R, Torre C, et al.combination of farnesyl transferase inhibitor (tipifarnib) with perifosine induces apoptosis through phos-pdk1 in human lymphoma and leukemia cell lines. ASH Annu Meet Abstr 2005;106(11):1488
88. Mollinedo F, de la Iglesia-Vicente J, Gajate C, et al. In vitro and in vivo selective antitumor activity of edelfosine against mantle cell lymphoma and chronic lymphocytic leukemia involving lipid rafts. Clin Cancer Res 2010;16(7):2046-54
89. Friedman DR, Davis PH, Lanasa MC, et al. Pre-clinical and interim results of a phase ii trial of perifosine in patients with relapsed or refractory chronic lymphocytic leukemia (cll). ASH Annu Meet Abstr 2010;116(21):1842
90. Guidetti A, Viviani S, Marchiano A, et al. Dual targeted therapy with the akt inhibitor perifosine and the multikinase inhibitor sorafenib in patients with relapsed/refractory lymphomas: Final results of a phase ii trial. ASH Annu Meet Abstr 2012;120(21):3679
91. Tong Y, Liu YY, You LS, et al. Perifosine induces protective autophagy and upregulation of atg5 in human chronic myelogenous leukemia cells in vitro. Acta Pharmacol Sin 2012;33(4):542-50
92. Bendell JC, Evin TJ, Senzer NN, et al. Results of the x-pect study: a phase iii randomized double-blind, placebo-controlled study of perifosine plus capecitabine (p-cap) versus placebo plus capecitabine (cap) in patients (pts) with refractory metastatic colorectal cancer (mcrc). J Clin Oncol 2012;30(Suppl):abstract LBA3501
93. Aeterna Zentaris, Inc. Aeterna zentaris to discontinue phase 3 trial in multiple myeloma with perifosine following data safety monitoring board recommendation. Press Release (2013). Available from: http://www.aezsinc.com/en/ page.php?p=60&q=550
94. Bendell JC, Nemunaitis J, Vukelja SJ, et al. Randomized placebo-controlled phase ii trial of perifosine plus capecitabine as second-or third-line therapy in patients with metastatic colorectal cancer. J Clin Oncol 2011;29(33):4394-400
95. Richardson PG, Wolf J, Jakubowiak A, et al. Perifosine plus bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma previously treated with bortezomib: results of a multicenter phase i/ii trial. J Clin Oncol 2011;29(32):4243-9
96. Martelli AM, Nyakern M, Tabellini G, et al. Phosphoinositide 3-kinase/akt signaling pathway and its therapeutical implications for human acute myeloid leukemia. Leukemia 2006;20(6):911-28
97. Park S, Chapuis N, Tamburini J, et al. Role of the pi3k/akt and mtor signaling pathways in acute myeloid leukemia. Haematologica 2010;95(5):819-28
98. U.S. National Institutes of Health. Available from: www.Clinicaltrials. gov [Last accessed on 15 March 2013]
99. Cantley LC, Neel BG. New insights into tumor suppression: Pten suppresses tumor formation by restraining the phosphoinositide 3-kinase/akt pathway. Proc Natl Acad Sci U S A 1999;96(8):4240-5
100. Liu P, Cheng H, Roberts TM, et al. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Dis 2009;8(8):627-44