Current view on the mechanism of action of Perifosine in cancer

Anti-Cancer Agents in Medicinal Chemistry

Volumn 14, Issue 4, 2014, Pages 629-635

  Fensterle, Joachim ^a   Aicher, Babette ^a   Seipelt, Irene ^a   Teifel, Michael ^a   Engel, Juergen ^a  

^a Aeterna Zentaris ^*  (Germany)

Author keywords

APL miltefosine; Cancer; Perifosine

Indexed keywords

7 HYDROXYSTAUROSPORINE; BORTEZOMIB; CAPECITABINE; CETUXIMAB; CISPLATIN; DEXAMETHASONE; ERLOTINIB; FAS ANTIGEN; I KAPPA B KINASE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; LENALIDOMIDE; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; MILTEFOSINE; PERIFOSINE; PHOSPHATIDYLINOSITOL 3, 4, 5 TRISPHOSPHATE; PHOSPHATIDYLINOSITOL 3, 4, 5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEIN KINASE B; PROTEIN P53; RAPAMYCIN; STRESS ACTIVATED PROTEIN KINASE; UNCLASSIFIED DRUG;

ANTINEOPLASTIC ACTIVITY; CANCER STEM CELL; DRUG MECHANISM; DRUG TARGETING; DRUG TUMOR LEVEL; GLIOMA; HUMAN; LIPID MEMBRANE; LIPID METABOLISM; LIPID RAFT; MOLECULARLY TARGETED THERAPY; MULTIPLE MYELOMA; NEOPLASM; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROSTATE CANCER; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; ANTINEOPLASTIC AGENTS; APOPTOSIS; CELL LINE, TUMOR; CELL MEMBRANE; HUMANS; LIPID METABOLISM; MEMBRANE MICRODOMAINS; NEOPLASMS; NEOPLASTIC STEM CELLS; PHOSPHORYLCHOLINE; PROTO-ONCOGENE PROTEINS C-AKT; RECEPTORS, DEATH DOMAIN; SIGNAL TRANSDUCTION;

EID: 84907509887     PISSN: 18715206     EISSN: 18755992     Source Type: Journal    
DOI: 10.2174/1871520614666140309225912     Document Type: Review

References (78)

1. Engel, J.; Hilgard, P.; Klenner, T.; Kutscher, B.; Nossner, G.; Traiser, M.; Voss, V. Perifosine. Drugs Fut., 2000, 25(12), 1257.
2. Eibl, H.; Unger, C. Hexadecylphosphocholine: A new and selective antitumor drug. Cancer Treat. Rev., 1990, 17, 233-242.
3. Croft, S.L.; Engel, J. Miltefosine--discovery of the antileishmanial activity of phospholipid derivatives. Trans. R. Soc. Trop. Med. Hyg., 2006, 100(Suppl 1), S4-S8.
4. Sindermann, H.; Enge, L.J. Development of miltefosine as an oral treatment for leishmaniasis. Trans. R. Soc. Trop. Med. Hyg., 2006, 100(Suppl 1), S17-S20.
5. Hilgard, P.; Klenner, T.; Stekar, J.; Nossner, G.; Kutscher, B.; Engel, J. D-21266, a new heterocyclic alkylphospholipid with antitumour activity. Eur. J. Cancer, 1997, 33, 442-446.
6. Vink, S.R.; Schellens, J.H.; Van Blitterswijk, W.J.; Verheij, M. Tumor and normal tissue pharmacokinetics of perifosine, an oral anti-cancer alkylphospholipid. Invest New Drugs, 2005, 23, 279-286.
7. Unger, C.; Berdel, W.; Hanauske, A.R.; Sindermann, H.; Enge, L.J.; Mross, K. First-time-in-man and pharmacokinetic study of weekly oral perifosine in patients with solid tumours. Eur. J. Cancer, 2010, 46, 920-925.
8. Gills, J.J.; Dennis, P.A. Perifosine: Update on a novel Akt inhibitor. Curr. Oncol. Rep., 2009, 11, 102-110.
9. Porta, C.; Figlin, R.A. Phosphatidylinositol-3-kinase/Akt signaling pathway and kidney cancer, and the therapeutic potential of phosphatidylinositol-3-kinase/Akt inhibitors. J. Urol., 2009, 182, 2569-2577.
10. Belcher, O.J.; Trippett, T.M.; Kolesar, J.; Gilheeney, S.; Jiang, Z.; Khakoo, Y.; Lyden, D.; Sima, C.; Modak, S.; Kushner, B.; Kramer, K.; Haque, S.; Cheung, N.-K.; Holland, E.C.; Dunkel, I. Phase I study of single agent perifosine for recurrent pediatric solid tumors. JCO, 2010 ASCO Annual Meeting Proceedings (Post-Meeting Edition), 2010, 28(Suppl 15), 9540
11. LoPiccolo, J.; Blumenthal, G.M.; Bernstein, W.B.; Dennis, P.A. Targeting the PI3K/Akt/mTOR pathway: Effective combinations and clinical considerations. Drug Resist. Updat., 2008, 11, 32-50.
12. Liao, Y.; Hung, M.C. Physiological regulation of Akt activity and stability. Am. J. Transl. Res., 2010, 2, 19-42.
13. Manning, B.D.; Cantley, L.C. AKT/PKB signaling: navigating downstream. Cell, 2007, 129, 1261-1274.
14. Lindsley, C.W.; Barnett, S.F.; Yaroschak, M.; Bilodeau, M.T.; Layton, M.E. Recent progress in the development of ATP-competitive and allosteric Akt kinase inhibitors. Curr. Top. Med. Chem., 2007, 7, 1349-1363.
15. Kondapaka, S.B.; Singh, S.S.; Dasmahapatra, G.P.; Sausville, E.A.; Roy, K.K. Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation. Mol. Cancer Ther., 2003, 2, 1093-1103.
16. Ruiter, G.A.; Zerp, S.F.; Bartelink, H.; Van Blitterswijk, W.J.; Verheij, M. Anti-cancer alkyl-lysophospholipids inhibit the phosphatidylinositol 3-kinase-Akt/PKB survival pathway. Anticancer Drugs, 2003, 14, 167-173.
17. Momota, H.; Nerio, E.; Holland, E.C. Perifosine inhibits multiple signaling pathways in glial progenitors and cooperates with temozolomide to arrest cell proliferation in gliomas in vivo. Cancer Res., 2005, 65, 7429-7435.
18. Rahmani, M.; Reese, E.; Dai, Y.; Bauer, C.; Payne, S.G.; Dent, P.; Spiegel, S.; Grant, S. 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, 2422-2432.
19. Nyakern, M.; Cappellini, A.; Mantovani, I.; Martelli, A.M. 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, 1559-1570.
20. Chiarini, F.; Del, S.M.; Mongiorgi, S.; Gaboardi, G.C.; Cappellini, A.; Mantovani, I.; Follo, M.Y.; McCubrey, J.A.; Martelli, A.M. 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, 1106-1116.
21. Papa, V.; Tazzari, P.L.; Chiarini, F.; Cappellini, A.; Ricci, F.; Billi, A.M.; Evangelisti, C.; Ottaviani, E.; Martinelli, G.; Testoni, N.; McCubrey, J.A.; Martelli, A.M. Proapoptotic activity and chemosensitizing effect of the novel Akt inhibitor perifosine in acute myelogenous leukemia cells. Leukemia, 2008, 22, 147-160.
22. Tazzari, P.L.; Tabellini, G.; Ricci, F.; Papa, V.; Bortul, R.; Chiarini, F.; Evangelisti, C.; Martinelli, G.; Bontadini, A.; Cocco, L.; McCubrey, J.A.; Martelli, A.M. Synergistic proapoptotic activity of recombinant TRAIL plus the Akt inhibitor Perifosine in acute myelogenous leukemia cells. Cancer Res., 2008, 68, 9394-9403.
23. Rahmani, M.; Anderson, A.; Habibi, J.R.; Crabtree, T.R.; Mayo, M.; Harada, H.; Ferreira-Gonzalez, A.; Dent, P.; Grant, S. 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, 4507-4516.
24. Caron, R.W.; Yacoub, A.; Li, M.; Zhu, X.; Mitchell, C.; Hong, Y.; Hawkins, W.; Sasazuki, T.; Shirasawa, S.; Kozikowski, A.P.; Dennis, P.A.; Hagan, M.P.; Grant, S.; Dent, P. 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., 2005, 4, 257-270.
25. Hideshima, T.; Catley, L.; Yasui, H.; Ishitsuka, K.; Raje, N.; Mitsiades, C.; Podar, K.; Munshi, N.C.; Chauhan, D.; Richardson, P.G.; Anderson, K.C. Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood, 2006, 107, 4053-4062.
26. Hideshima, T.; Catley, L.; Raje, N.; Chauhan, D.; Podar, K.; Mitsiades, C.; Tai, Y.T.; Vallet, S.; Kiziltepe, T.; Ocio, E.; Ikeda, H.; Okawa, Y.; Hideshima, H.; Munshi, N.C.; Yasui, H.; Richardson, P.G.; Anderson, K.C. Inhibition of Akt induces significant downregulation of survivin and cytotoxicity in human multiple myeloma cells. Br. J. Haematol., 2007, 138, 783-791.
27. Leleu, X.; Jia, X.; Runnels, J.; Ngo, H.T.; Moreau, A.S.; Farag, M.; Spencer, J.A.; Pitsillides, C.M.; Hatjiharissi, E.; Roccaro, A.; O'Sullivan, G.; McMillin, D.W.; Moreno, D.; Kiziltepe, T.; Carrasco, R.; Treon, S.P.; Hideshima, T.; Anderson, K.C.; Lin, C.P.; Ghobrial, I.M. The Akt pathway regulates survival and homing in Waldenstrom macroglobulinemia. Blood, 2007, 110, 4417-4426.
28. Ayala, G.; Yan, J.; Li, R.; Ding, Y.; Thompson, T.C.; Mims, M.P.; Hayes, T.G.; MacDonnell, V.; Lynch, R.G.; Frolov, A.; Miles, B.J.; Wheeler, T.M.; Harper, J.W.; Tsai, M.J.; Ittmann, M.M.; Kadmon, D. Bortezomib-mediated inhibition of steroid receptor coactivator-3 degradation leads to activated Akt. Clin. Cancer Res., 2008, 14, 7511-7518.
29. Festuccia, C.; Gravina, G.L.; Muzi, P.; Millimaggi, D.; Dolo, V.; Vicentini, C.; Bologna, M. Akt down-modulation induces apoptosis of human prostate cancer cells and synergizes with EGFR tyrosine kinase inhibitors. Prostate, 2008, 68, 965-974.
30. Vinall, R.L.; Hwa, K.; Ghosh, P.; Pan, C.X.; Lara, P.N. Jr.; De Vere White, R.W. Combination treatment of prostate cancer cell lines with bioactive soy isoflavones and perifosine causes increased growth arrest and/or apoptosis. Clin. Cancer Res., 2007, 13, 6204-6216.
31. Engel, J.B.; Honig, A.; Schonhals, T.; Weidler, C.; Hausler, S.; Krockenberger, M.; Grunewald, T.G.; Dombrowski, Y.; Rieger, L.; Dietl, J.; Wischhusen, J. Perifosine inhibits growth of human experimental endometrial cancers by blockade of AKT phosphorylation. Eur. J. Obstet. Gynecol. Reprod. Biol., 2008, 141, 64-69.
32. Engel, J.B.; Schonhals, T.; Hausler, S.; Krockenberger, M.; Schmidt, M.; Horn, E.; Koster, F.; Dietl, J.; Wischhusen, J.; Honig, A. Induction of programmed cell death by inhibition of AKT with the alkylphosphocholine perifosine in in vitro models of platinum sensitive and resistant ovarian cancers. Arch. Gynecol. Obstet., 2011, 283, 603-610.
33. Korkaya, H.; Paulson, A.; Charafe-Jauffret, E.; Ginestier, C.; Brown, M.; Dutcher, J.; Clouthier, S.G.; Wicha, M.S. Regulation of mammary stem/progenitor cells by PTEN/Akt/beta-catenin signaling. PLoS. Biol., 2009, 7, e1000121.
34. Fu, L.; Kim, Y.A.; Wang, X.; Wu, X.; Yue, P.; Lonial, S.; Khuri, F.R.; Sun, S.Y. Perifosine inhibits mammalian target of rapamycin signaling through facilitating degradation of major components in the mTOR axis and induces autophagy. Cancer Res., 2009, 69, 8967-8976.
35. Kumar, A.; Fillmore, H.L.; Kadian, R.; Broaddus, W.C.; Tye, G.W.; Van Meter, T.E. The alkylphospholipid perifosine induces apoptosis and p21-mediated cell cycle arrest in medulloblastoma. Mol. Cancer Res., 2009, 7, 1813-1821.
36. Hennessy, B.T.; Lu, Y.; Poradosu, E.; Yu, Q.; Yu, S.; Hall, H.; Carey, M.S.; Ravoori, M.; Gonzalez-Angulo, A.M.; Birch, R.; Henderson, I.C.; Kundra, V.; Mills, G.B. Pharmacodynamic markers of perifosine efficacy. Clin. Cancer Res., 2007, 13, 7421-7431.
37. De la Pena, L.; Burgan, W.E.; Carter, D.J.; Hollingshead, M.G.; Satyamitra, M.; Camphausen, K.; Tofilon, P.J. Inhibition of Akt by the alkylphospholipid perifosine does not enhance the radiosensitivity of human glioma cells. Mol. Cancer Ther., 2006, 5, 1504-1510.
38. Zhang, L.; Lee, K.C.; Bhojani, M.S.; Khan, A.P.; Shilman, A.; Holland, E.C.; Ross, B.D.; Rehemtulla, A. Molecular imaging of Akt kinase activity. Nat. Med., 2007, 13, 1114-1119.
39. Van Blitterswijk, W.J.; Verheij, M. Anticancer alkylphospholipids: mechanisms of action, cellular sensitivity and resistance, and clinical prospects. Curr. Pharm. Des., 2008, 14, 2061-2074.
40. Zerp, S.F.; Vink, S.R.; Ruiter, G.A.; Koolwijk, P.; Peters, E.; Van der Luit, A.H.; De, J.D.; Budde, M.; Bartelink, H.; Van Blitterswijk, W.J.; Verheij, M. Alkylphospholipids inhibit capillary-like endothelial tube formation in vitro: antiangiogenic properties of a new class of antitumor agents. Anticancer Drugs, 2008, 19, 65-75.
41. Mollinedo, F.; Gajate, C. Lipid rafts, death receptors and CASMERs: new insights for cancer therapy. Future. Oncol., 2010, 6, 491-494.
42. Gajate, C.; Mollinedo, F. The antitumor ether lipid ET-18-OCH[3] induces apoptosis through translocation and capping of Fas/CD95 into membrane rafts in human leukemic cells. Blood, 2011, 98, 3860-3863.
43. Gajate, C.; Mollinedo, F. Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts. Blood, 2007, 109, 711-719.
44. Mollinedo, F.; De La Iglesia-Vicente J, Gajate, C.; Estella-Hermoso De, M.A.; Villa-Pulgarin, J.A.; Campanero, M.A.; Blanco-Prieto, M.J. Lipid raft-targeted therapy in multiple myeloma. Oncogene, 2010, 29, 3748-3757.
45. Mollinedo, F.; De La, I.; Gajate, C.; Estella-Hermoso De, M.A.; Villa-Pulgarin, J.A.; De, F.M.; Roue, G.; Gil, J.; Colomer, D.; Campanero, M.A.; Blanco-Prieto, M.J. 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, 2046-2054.
46. Van Der Luit, A.H.; Budde, M.; Ruurs, P.; Verheij, M.; Van Blitterswijk, W.J. Alkyl-lysophospholipid accumulates in lipid rafts and induces apoptosis via raft-dependent endocytosis and inhibition of phosphatidylcholine synthesis. J. Biol. Chem., 2002, 277, 39541-39547.
47. Van Der Luit, A.H.; Budde, M.; Verheij, M.; Van Blitterswijk, W.J. Different modes of internalization of apoptotic alkyl-lysophospholipid and cell-rescuing lysophosphatidylcholine. Biochem. J., 2003, 374, 747-753.
48. Van der Luit, A.H.; Vink, S.R.; Klarenbeek, J.B.; Perrissoud, D.; Solary, E.; Verheij, M.; Van Blitterswijk, W.J. A new class of anticancer alkylphospholipids uses lipid rafts as membrane gateways to induce apoptosis in lymphoma cells. Mol. Cancer Ther., 2007, 6, 2337-2345.
49. Mollinedo, F.; Gajate, C. Lipid rafts and clusters of apoptotic signaling molecule-enriched rafts in cancer therapy. Future. Oncol., 2010, 6, 811-821.
50. Carrasco, M.P.; Jimenez-Lopez, J.M.; Rios-Marco, P.; Segovia, J.L.; Marco, C. Disruption of cellular cholesterol transport and homeostasis as a novel mechanism of action of membrane-targeted alkylphospholipid analogues. Br. J. Pharmacol., 2010, 160, 355-366.
51. Jimenez-Lopez, J.M.; Rios-Marco, P.; Marco, C.; Segovia, J.L.; Carrasco, M.P. Alterations in the homeostasis of phospholipids and cholesterol by antitumor alkylphospholipids. Lipids Health Dis., 2010, 9, 33.
52. De Laurentiis, A.; Donovan, L.; Arcaro, A. Lipid rafts and caveolae in signaling by growth factor receptors. Open. Biochem. J., 2007, 1, 12-32.
53. Van der Luit, A.H.; Vink, S.R.; Klarenbeek, J.B.; Perrissoud, D.; Solary, E.; Verheij, M.; Van Blitterswijk, W.J. A new class of anticancer alkylphospholipids uses lipid rafts as membrane gateways to induce apoptosis in lymphoma cells. Mol. Cancer Ther., 2007, 6, 2337-2345.
54. Vink, S.R.; Van der Luit, A.H.; Klarenbeek, J.B.; Verheij, M.; Van Blitterswijk, W.J. Lipid rafts and metabolic energy differentially determine uptake of anti-cancer alkylphospholipids in lymphoma versus carcinoma cells. Biochem. Pharmacol., 2007, 74, 1456-1465.
55. Munoz-Martinez, F.; Torres, C.; Castanys, S.; Gamarro, F. The anti-tumor alkylphospholipid perifosine is internalized by an ATP-dependent translocase activity across the plasma membrane of human KB carcinoma cells. Biochim. Biophys. Acta, 2008, 1778, 530-540.
56. Munoz-Martinez, F.; Torres, C.; Castanys, S.; Gamarro, F. CDC50A plays a key role in the uptake of the anticancer drug perifosine in human carcinoma cells. Biochem. Pharmacol., 2010, 80, 793-800.
57. Fu, L.; Lin, Y.D.; Elrod, H.A.; Yue, P.; Oh, Y.; Li, B.; Tao, H.; Chen, G.Z.; Shin, D.M.; Khuri, F.R.; Sun, S.Y. Disruption of cellular cholesterol transport and homeostasis as a novel mechanism of action of membrane-targeted alkylphospholipid analogues. Mol. Cancer, 2010, 9, 315.
58. Gajate, C.; Santos-Beneit, A.; Modolell, M.; Mollinedo, F. Involvement of c-Jun NH2-terminal kinase activation and c-Jun in the induction of apoptosis by the ether phospholipid 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine. Mol. Pharmacol., 1998, 53, 602-612.
59. Li, X.; Luwor, R.; Lu, Y.; Liang, K.; Fan, Z. Enhancement of antitumor activity of the anti-EGF receptor monoclonal antibody cetuximab/C225 by perifosine in PTEN-deficient cancer cells. Oncogene, 2006, 25, 525-535.
60. Ruiter, G.A.; Zerp, S.F.; Bartelink, H.; Van Blitterswijk, W.J.; Verheij, M. Alkyl-lysophospholipids activate the SAPK/JNK pathway and enhance radiation-induced apoptosis. Cancer Res., 1999, 59, 2457-2463.
61. Floryk, D.; Thompson, T.C. Perifosine induces differentiation and cell death in prostate cancer cells. Cancer Lett., 2008, 266, 216-226.
62. Leleu, X.; Eeckhoute, J.; Jia, X.; Roccaro, A.M.; Moreau, A.S.; Farag, M.; Sacco, A.; Ngo, H.T.; Runnels, J.; Melhem, M.R.; Burwick, N.; Azab, A.; Azab, F.; Hunter, Z.; Hatjiharissi, E.; Carrasco, D.R.; Treon, S.P.; Witzig, T.E.; Hideshima, T.; Brown, M.; Anderson, K.C.; Ghobrial, I.M. Targeting NF-kappaB in Waldenstrom macroglobulinemia. Blood, 2008, 111, 5068-5077.
63. Patel, V.; Lahusen, T.; Sy, T.; Sausville, E.A.; Gutkind, J.S.; Senderowicz, A.M. 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. Cancer Res., 2002, 62, 1401-1409.
64. Bell, H.S.; Ryan, K.M. Targeting the p53 family for cancer therapy: 'big brother' joins the fight. Cell Cycle, 2007, 6, 1995-2000.
65. David, E.; Sinha, R.; Chen, J.; Sun, S.Y.; Kaufman, J.L.; Lonial, S. Perifosine synergistically enhances TRAIL-induced myeloma cell apoptosis via up-regulation of death receptors. Clin. Cancer Res., 2008, 14, 5090-5098.
66. Elrod, H.A.; Lin, Y.D.; Yue, P.; Wang, X.; Lonial, S.; Khuri, F.R.; Sun, S.Y. The alkylphospholipid perifosine induces apoptosis of human lung cancer cells requiring inhibition of Akt and activation of the extrinsic apoptotic pathway. Mol. Cancer Ther., 2007, 6, 2029-2038.
67. Fei, H.R.; Chen, G.; Wang, J.M.; Wang, F.Z. Perifosine induces cell cycle arrest and apoptosis in human hepatocellular carcinoma cell lines by blockade of Akt phosphorylation. Cytotechnology, 2010, 62, 449-460.
68. Jung, C.H.; Ro, S.H.; Cao, J.; Otto, N.M.; Kim, D.H. Mtor regulation of autophagy. FEBS Lett., 2010, 584, 1287-1295.
69. Chen, S.; Rehman, S.K.; Zhang, W.; Wen, A.; Yao, L.; Zhang, J. Autophagy is a therapeutic target in anticancer drug resistance. Biochim. Biophys. Acta, 2010, 1806, 220-229.
70. Nencioni, A.; Grunebach, F.; Patrone, F.; Ballestrero, A.; Brossart, P. Proteasome inhibitors: Antitumor effects and beyond. Leukemia, 2007, 21, 30-36.
71. Huston, A.; Leleu, X.; Jia, X.; Moreau, A.S.; Ngo, H.T.; Runnels, J.; Anderson, J.; Alsayed, Y.; Roccaro, A.; Vallet, S.; Hatjiharissi, E.; Tai, Y.T.; Sportelli, P.; Munshi, N.; Richardson, P.; Hideshima, T.; Roodman, D.G.; Anderson, K.C.; Ghobrial, I.M. Targeting Akt and heat shock protein 90 produces synergistic multiple myeloma cell cytotoxicity in the bone marrow microenvironment. Clin. Cancer Res., 2008, 14, 865-874.
72. Vink, S.R.; Lagerwerf, S.; Mesman, E.; Schellens, J.H.; Begg, A.C.; Van Blitterswijk, W.J.; Verheij, M. Radiosensitization of squamous cell carcinoma by the alkylphospholipid perifosine in cell culture and xenografts. Clin. Cancer Res., 2006, 12, 1615-1622.
73. Vink, S.R.; Van Blitterswijk, W.J.; Schellens, J.H.; Verheij, M. Rationale and clinical application of alkylphospholipid analogues in combination with radiotherapy. Cancer Treat. Rev., 2007, 33, 191-202.
74. Zhang, M.; Atkinson, R.L.; Rosen, J.M. Selective targeting of radiation-resistant tumor-initiating cells. Proc. Natl. Acad. Sci. USA, 2010, 107, 3522-3527.
75. Cirstea, D.; Hideshima, T.; Rodig, S.; Santo, L.; Pozzi, S.; Vallet, S.; Ikeda, H.; Perrone, G.; Gorgun, G.; Patel, K.; Desai, N.; Sportelli, P.; Kapoor, S.; Vali, S.; Mukherjee, S.; Munshi, N.C.; Anderson, K.C.; Raje, N. Dual inhibition of akt/mammalian target of rapamycin pathway by nanoparticle albumin-bound-rapamycin and perifosine induces antitumor activity in multiple myeloma. Mol. Cancer Ther., 2010, 9, 963-975.
76. Pitter, K.L.; Galban, C.J.; Galban, S.; Tehrani, O.S.; Li, F.; Charles, N.; Bradbury, M.S.; Becher, O.J.; Chenevert, T.L.; Rehemtulla, A.; Ross, B.D.; Holland, E.C.; Hambardzumyan, D. Perifosine and CCI 779 co-operate to induce cell death and decrease proliferation in PTEN-intact and PTEN-deficient PDGF-driven murine glioblastoma. PLoS. One, 2011, 6, e14545.
77. Dasmahapatra, G.P.; Didolkar, P.; Alley, M.C.; Ghosh, S.; Sausville, E.A.; Roy, K.K. 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., 2004, 10, 5242-5252.
78. Alison, M.R.; Islam, S.; Wright, N.A. Stem cells in cancer: Instigators and propagators? J. Cell Sci., 2010, 123, 2357-2368.