Targeting ion channels in leukemias: A new challenge for treatment

Current Medicinal Chemistry

Volumn 19, Issue 5, 2012, Pages 683-696

  Arcangeli, A ^a,b   Pillozzi, S ^a   Becchetti, A ^c  

^a UNIVERSITY OF FLORENCE   (Italy)

^b ISTITUTO TOSCANO TUMORI   (Italy)

^c UNIVERSITY OF MILANO BICOCCA   (Italy)

Author keywords

Antileukemic drugs; Chemoresistance; Combined treatment; Conformational states; Ion channels; Kv11.1; Leukemia; Mechanisms of channel block; Stroma; Therapy

Indexed keywords

1 [2 (6 METHYL 2 PYRIDYL)ETHYL] 4 (4 METHYLSULFONYLAMINOBENZOYL)PIPERIDINE; 1 [N,O BIS(5 ISOQUINOLINESULFONYL) N METHYLTYROSYL] 4 PHENYLPIPERAZINE; A 438079; ANTISENSE OLIGONUCLEOTIDE; ASTEMIZOLE; CARDENOLIDE DERIVATIVE; CHEMOKINE RECEPTOR; CHLOROTOXIN; CISAPRIDE; CYCLOPHOSPHAMIDE; ERYTHROMYCIN; GAP JUNCTION PROTEIN; GROWTH FACTOR; IMATINIB; IMIPRAMINE; INTEGRIN RECEPTOR; ION CHANNEL; N METHYL N [2 [METHYL(1 METHYL 1H BENZIMIDAZOL 2 YL)AMINO]ETHYL] 4 [(METHYLSULFONYL)AMINO]BENZENESULFONAMIDE; POTASSIUM CHANNEL BLOCKING AGENT; POTASSIUM CHANNEL HERG; PROTEIN TYROSINE KINASE INHIBITOR; PURINERGIC RECEPTOR; RITUXIMAB; ROSCOVITINE; SCORPION VENOM; SERTINDOLE; SMALL INTERFERING RNA; TERFENADINE; TRAM 34; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ACUTE GRANULOCYTIC LEUKEMIA; ACUTE LYMPHOBLASTIC LEUKEMIA; APOPTOSIS; ARTICLE; BONE MARROW CELL; CANCER COMBINATION CHEMOTHERAPY; CANCER INVASION; CELL ADHESION; CELL PROLIFERATION; CELL TYPE; CELL VOLUME; CHRONIC LYMPHATIC LEUKEMIA; CHRONIC MYELOID LEUKEMIA; CONFORMATIONAL TRANSITION; DRUG BINDING; DRUG CYTOTOXICITY; EXTRACELLULAR MATRIX; HUMAN; ION TRANSPORT; LARGE CELL LYMPHOMA; LEUKEMIA; LEUKEMIA CELL; METASTASIS; MYELODYSPLASTIC SYNDROME; NONHUMAN; PHENOTYPE; PLEIOTROPY; PROGNOSIS; PROTEIN EXPRESSION; STEM CELL; STROMA CELL; THERAPY RESISTANCE; TUMOR DIFFERENTIATION; TUMOR GENE; TUMOR GROWTH;

ANIMALS; ETHER-A-GO-GO POTASSIUM CHANNELS; HUMANS; ION CHANNELS; LEUKEMIA; LEUKEMIA, MYELOID, ACUTE; MOLECULAR TARGETED THERAPY; PRECURSOR CELL LYMPHOBLASTIC LEUKEMIA-LYMPHOMA;

EID: 84857779494     PISSN: 09298673     EISSN: 1875533X     Source Type: Journal    
DOI: 10.2174/092986712798992093     Document Type: Article

References (143)

1. Greer, J.P.; Foerster, J.; Rodgers, G.; Paraskevas, F.; Glader, B.; Arber, D. & Means, R.T. (2008) Wintrobe's Clinical Hematology (12th edition), Lippincott Williams & Wilkins, ISBN: 978-0-7817-6507-7.
2. Kantarjian, H; O'Brien, S.; Cortes, J.; Wierda, W.; Faderl, S.; Garcia-Manero, G.; Issa, J.P.; Estey, E.; Keating, M.; Freireich, E.J. Therapeutic advances in leukemia and myelodysplastic syndrome over the past 40 years. Cancer, 2008, 113, 1933-1952.
3. Gnoni, A.; Marech, I.; Silvestris, N.; Vacca, A.; Lorusso, V. Desatinib: An anti-tumour agent via Src inhibition. Curr. Drug Targets, 2011, 12, 563-578.
4. O'Gorman, D.M.; Cotter, T.G. Molecular signals in anti-Apoptotic survival pathways. Leukemia, 2001, 15(1), 21-34. (Pubitemid 32140323)
5. Ross, D.D. Novel mechanisms of drug resistance in leukemia. Leukemia, 2000, 14(3), 467-473. (Pubitemid 30142873)
6. Meads, M.B.; Gatenby, R.A.; Dalton, W.S. Environment-mediated drug resistance: A major contributor to minimal residual disease. Nat. Rev. Cancer., 2009, 9(9), 665-674.
7. Tabe, Y.; Konopleva, M.; Kondo, Y.; Contractor, R.; Tsao, T.; Konoplev, S.; Shi, Y.; Ling, X.; Watt, J.C.; Tsutsumi-Ishii, Y.; Ohsaka, A.; Nagaoka, I.; Issa, J.P.; Kogan, S.C.; Andreeff, M. PPARgamma-Active triterpenoid CDDO enhances ATRA-induced differentiation in APL. Cancer Biol. Ther., 2007, 6(12), 1967-1977. (Pubitemid 351590411)
8. Arcangeli, A.; Becchetti, A. Complex functional interaction between integrin receptors and ion channels. Trends Cell Biol., 2006, 16(12), 631-639. (Pubitemid 44809885)
9. Arcangeli, A.; Crociani, O.; Lastraioli, E.; Masi, A.; Pillozzi, S.; Becchetti, A. Targeting ion channels in cancer: A novel frontier in antineoplastic therapy. Curr Med Chem., 2009, 16(1), 66-93.
10. Becchetti, A.; Pillozzi, S.; Morini, R.; Nesti, E.; Arcangeli A. New insights into the regulation of ion channels by integrins. Int. Rev. Cell Mol. Biol., 2010, 279, 135-190.
11. Cahalan, M.D.; Chandy, K.G.; DeCoursey, T.E.; Gupta, S. A voltage-gated potassium channel in human T lymphocytes. J. Physiol., 1985, 358, 197-237. (Pubitemid 15150542)
12. Lu, L.; Yang, T.; Markakis, D.; Guggino, W. B.; Craig, R. W. Alterations in a voltage-gated K+ current during the differentiation of ML-1 human myeloblastic leukemia cells. J. Membr. Biol., 1993, 132, 267-274. (Pubitemid 23098659)
13. Xu, B.; Wilson, B. A.; Lu, L. Induction of human myeloblastic ML-1 cell G1 arrest by suppression of K+ channel activity. Am. J. Physiol., 1996, 271, C2037-2044.
14. Wang, L.; Xu, B.; White, R. E.; Lu, L. Growth factor-mediated K+ channel activity associated with human myeloblastic ML-1 cell proliferation. Am. J. Physiol., 1997, 273, C1657-1665.
15. Xu, D.; Wang, L.; Dai, W.; Lu, L. A requirement for K+ channel activity in growth factor-mediated extracellular signal-regulated kinase activation in human myeloblastic leukemia ML-1 cells. Blood, 1999, 94, 139-145. (Pubitemid 29300142)
16. Becchetti, A. Ion channels and transporters in cancer. 1. Ion channels and cell proliferation in cancer. Am. J. Physiol. Cell. Physiol., 2011, 301, C255-C265.
17. Straube, S.; Parekh, A.B. Inwardly rectifying potassium currents in rat basophilic leukaemia (RBL-1) cells: Regulation by spermine and implications for store-operated calcium influx. Pflugers Arch., 2002, 444, 389-396. (Pubitemid 35447413)
18. Wang, J.; Xu, Y.Y.; Gongora, R.; Warnock, D.G.; Ma, H.P. An intermediateconductance Ca2+-Activated K+ channel mediates B lymphoma cell cycle progression induced by serum. Pflugers Arch., 2007, 454, 945-956. (Pubitemid 47338459)
19. Smith, G.A.M.; Tsui, H.; Newell, E.W.; Jiang, X.; Zhu, X.; Tsui, F. W. L.; Schlichter, L.C. Functional up-regulation of HERG K+ channels in neoplastic hemopoietic cells. J. Biol. Chem., 2002, 277, 18528-18534. (Pubitemid 34952403)
20. Pillozzi, S.; Brizzi, M. F.; Balzi, M.; Crociani, O.; Cherubini, A.; Guasti, L.; Bartolozzi, B.; Becchetti, A.; Wanke, E.; Bernabei, P. A.; Olivotto, M.; Pegoraro, L.; Arcangeli, A. HERG potassium channels are constitutively expressed in primary human acute myeloid leukemias and regulate cell proliferation of normal and leukemic hemopoietic progenitors. Leukemia, 2002, 16(9), 1791-1798.
21. Li, H.; Liu, L.; Guo, L.; Zhang, J.; Du, W.; Li, X.; Liu, W.; Chen X.; Huang S. HERG K+ channel expression in CD34+/CD38-/CD123(high) cells and primary leukemia cells and analysis of its regulation in leukemia cells. Int. J. Hematol., 2008, 87(4), 387-392.
22. Pardo, L.A. Voltage-gated potassium channels in cell proliferation. Physiology, 2004, 19, 285-292. (Pubitemid 39472640)
23. Agarwal, J.R.; Griesinger, F.; Stühmer, W.; Pardo, L.A. The potassium channel Ether à go-go is a novel prognostic factor with functional relevance in acute myeloid leukemia. Mol Cancer, 2010, 9(18), 1-16.
24. Arcangeli, A.; Wanke, E.; Olivotto, M.; Camagni, S.; Ferroni, A. Three types of ion channels are present on the plasma membrane of Friend erythroleukemia cells. Biochem. Biophys. Res. Commun., 1987, 146, 1450-1457.
25. Arcangeli, A.; Ricupero, L.; Olivotto, M. Commitment to differentiation of murine erythroleukemia cells involves a modulated plasma membrane depolarization through Ca2+-Activated K+ channels. J. Cell Physiol., 1987, 132, 387-400. (Pubitemid 18005465)
26. Arcangeli, A.; Becchetti, A.; Del Bene, M. R.; Wanke, E.; Olivotto, M. Fibronectin-integrin binding promotes hyperpolarization of murine erythroleukemia cells. Biochem. Biophys. Res. Commun., 1991, 177, 1266-1272.
27. Becchetti, A.; Arcangeli, A.; Del Bene, M. R.; Olivotto, M.; Wanke, E. Response to fibronectin-integrin interaction in leukaemia cells: Delayed enhancing of a K+ current. Proc. Biol. Sci., 1992, 248, 235-240.
28. Arcangeli, A.; Del Bene, M.R.; Poli, R.; Ricupero, L.; Olivotto, M. Mutual contact of murine erythroleukemia cells activates depolarizing cation channels, whereas contact with extracellular substrata activates hyperpolarizing Ca2+-dependent K+ channels. J. Cell. Physiol., 1989, 139, 1-8. (Pubitemid 19120263)
29. DeCoursey, T. E.; Kim, S. Y.; Silver, M. R.; Quandt, F.N. Ion channel expression in PMA-differentiated human THP-1 macro-phages. J. Membr. Biol., 1996, 152, 141-157. (Pubitemid 26266046)
30. Hofmann, G.; Bernabei, P.A.; Crociani, O.; Cherubini, A.; Guasti, L.; Pillozzi, S.; Lastraioli, E.; Polvani, S.; Bartolozzi, B.; Solazzo, V.; Gragnani, L.; Defilippi, P.; Rosati, B.; Wanke, E.; Olivotto, M.; Arcangeli, A. HERG K+ channels activation during beta(1) integrin-mediated adhesion to fibronectin induces an up-regulation of alpha(v)beta(3) integrin in the preosteoclastic leukemia cell line FLG 29.1. J. Biol. Chem., 2001, 276(7), 4923-4931.
31. Olsen, M.L.; Weaver, A. K.; Ritch, P. S.; Sontheimer, H. Modulation of glioma BK channels via erbB2. J. Neurosci. Res., 2005, 81, 179-189. (Pubitemid 41153331)
32. Pillozzi, S.; Brizzi, M. F.; Bernabei, P. A.; Bartolozzi, B.; Caporale, R.; Basile, V.; Boddi, V.; Pegoraro, L.; Becchetti, A.; Arcangeli, A. VEGFR-1 (FLT-1), beta1 integrin, and hERG K+ channel form a macromolecular signaling complex in acute myeloid leukemia: Role in cell migration and clinical outcome. Blood, 2007, 110, 1238-1250. (Pubitemid 47281422)
33. Crociani, O.; Guasti, L.; Balzi, M.; Becchetti, A.; Wanke, E.; Olivotto, M.; Wymore, R. S.; Arcangeli, A. Cell cycle-dependent expression of HERG1 and HERG1B isoforms in tumor cells. J. Biol. Chem., 2003, 278, 2947-2955. (Pubitemid 36801200)
34. Pottosin, I.I.; Bonales-Alatorre, E.; Valencia-Cruz, G.; Mendoza-Magaña, M.L.; Dobrovinskaya, O.R. TRESK-like potassium channels in leukemic T cells. Pflugers Arch., 2008, 456(6), 1037-1048.
35. Vasil'eva, I.O.; Neguliaev, IuA, Marakhova, I.I.; Semenova, S.B. TRPV5 and TRPV6 calcium channels in human T cells. Tsitologiia, 2008, 50(11), 953-957.
36. Heise, N., Palme, D., Misovic, M., Koka, S., Rudner, J., Lang, F., Salih, H.R., Huber, S.M., Henke, G. Non-selective cation channel-mediated Ca2+-entry and activation of Ca2+/calmodulin-dependent kinase II contribute to G2/M cell cycle arrest and survival of irradiated leukemia cells. Cell. Physiol. Biochem., 2010, 26(4-5), 597-608.
37. Kasinathan, R.S.; Föller, M.; Lang, C.; Koka, S.; Lang, F.; Huber, S.M. Oxidation induces ClC-3-dependent anion channels in human leukaemia cells. FEBS Lett., 2007, 581(28), 5407-5412. (Pubitemid 350101522)
38. Jiang B, Hattori N, Liu B, Kitagawa K, Inagaki C. Expression of swellingand/ or pH-regulated chloride channels (ClC-2, 3, 4 and 5) in human leukemic and normal immune cells. Life Sci., 2002, 70(12), 1383-1394. (Pubitemid 34159095)
39. Renaudo, A.; L'Hoste, S.; Guizouarn, H.; Borgèse, F.; Soriani, O. Cancer cell cycle modulated by a functional coupling between sigma-1 receptors and Clchannels. J. Biol. Chem., 2007, 282(4), 2259-2267. (Pubitemid 47076777)
40. Renaudo, A.; Watry, V.; Chassot, A.A.; Ponzio, G.; Ehrenfeld, J.; Soriani O. Inhibition of tumor cell proliferation by sigma ligands is associated with K+ Channel inhibition and p27kip1 accumulation. J. Pharmacol. Exp. Ther., 2004, 311(3), 1105-1114. (Pubitemid 39612717)
41. Nico, B.; Ribatti, D. Aquaporins in tumor growth and angiogenesis. Cancer Lett., 2010, 294, 135-138.
42. King, L.S.; Kozono D.; Agre, P. From structure to disease: The evolving tale of aquaporin biology. Nat. Rev. Cell. Mol. Biol., 2004, 5(9), 687-698. (Pubitemid 39208179)
43. Hachez, C., Chaumont, F. Aquaporins: A family of highly regulated multifunctional channels. Adv. Exp. Med. Biol., 2010, 679, 1-17.
44. Chae, Y.K.; Kang, S.K.; Kim, M.S.; Woo, J.; Lee, J.; Chang, S.; Kim, D.W.; Kim, M., Park, S., Kim, I.; Keam, B.; Rhee, J.; Koo, N.H.; Park, G.; Kim, S.H.; Jang, S.E.; Kweon, I.Y.; Sidransky, D.; Moon, C. Human AQP5 plays a role in the progression of chronic myelogenous leukemia (CML). PLoS One, 2008, 3(7), e2594.
45. Köles, L.; Fürst, S.; Illes, P. Purine ionotropic (P2X) receptors. Curr. Pharm. Des., 2007, 13(23), 2368-2384. (Pubitemid 47321570)
46. Solini, A.; Cuccato, S.; Ferrari, D.; Santini, E.; Gulinelli, S.; Callegari, M.G.; Dardano, A.; Faviana, P.; Madec, S.; Di Virgilio, F.; Monzani, F. Increased P2X7 receptor expression and function in thyroid papillary cancer: A new potential marker of the disease? Endocrinology, 2008, 149, 389-396.
47. Sun SH. Roles of P2X7 receptor in glial and neuroblastoma cells: The therapeutic potential of P2X7 receptor antagonists. Mol. Neurobiol., 2010, 41(2-3), 351-355.
48. Adinolfi, E.; Melchiorri, L.; Falzoni, S.; Chiozzi, P.; Morelli, A.; Tieghi, A.; Cuneo, A.; Castoldi, G.; Di Virgilio, F.; Baricordi, O.R. P2X7 receptor expression in evolutive and indolent forms of chronic B lymphocytic leukemia. Blood, 2002, 99(2), 706-708. (Pubitemid 34533113)
49. Zhang, X.; Meng, L.; He, B.; Chen, J.; Liu, P.; Zhao, J.; Zhang, Y.; Li, M.; An, D. The role of P2X7 receptor in ATP-mediated human leukemia cell death: Calcium influx-independent. Acta Biochim. Biophys. Sin. (Shanghai), 2009, 41(5), 362-369.
50. Zhang, X.J.; Zheng, G.G.; Ma, X.T.; Yang, Y.H.; Li, G., Rao; Q., Nie, K.; Wu, K.F. Expression of P2X7 in human hematopoietic cell lines and leukemia patients. Leuk. Res., 2004, 28(12), 1313-1322. (Pubitemid 39314411)
51. Chong, J.H.; Zheng, G.G.; Ma, Y.Y.; Zhang, H.Y.; Nie, K.; Lin, Y.M.; Wu, K.F. The hyposensitive N187D P2X7 mutant promotes malignant progression in nude mice. J .Biol. Chem., 2010, 285(46), 36179-36187.
52. Constantinescu, P.; Wang, B.; Kovacevic, K.; Jalilian. I; Bosman, G.J.; Wiley, J.S. & Sluyter, R. P2X7 receptor activation induces cell death and microparticle release in murine erythroleukemia cells. Biochim. Biophys. Acta, 2010, 1798(9), 1797-1804.
53. Maeda, S.; Tsukihara, T. Structure of the gap junction channel and its implications for its biological functions. Cell. Mol. Life Sci., 2011, 68, 1115-1129.
54. Foss, B.; Tronstad, K.J.; Bruserud, Ø. Connexin-based signaling in acute myelogenous leukemia (AML). Biochem. Biophys. Acta, 2010, 1798, 1-8.
55. Oviedo-Orta, E.; Evans, H.W. Gap junctions and connexin-mediated communication in the immune system. Biochem. Biophys. Acta Biomembr., 2004, 1662, 102-112. (Pubitemid 38366516)
56. Dorshkind, K.; Green, L.; Godwin, A.; Fletcher, W.H. Connexin-43-type gap junctions mediate communication between bone marrow stromal cells. Blood, 1993, 82, 38-45. (Pubitemid 23188744)
57. Cancelas, J.A.; Koevoet, W.L.M.; de Koning, A.E.; Mayen, A.E.M.; Rombouts, E.J.C.; Ploemacher, R.E. Connexin-43 gap junctions are involved in multiconnexin-expressing stromal support of hemopoietic progenitors and stem cells. Blood, 2000, 96, 498-505. (Pubitemid 30463368)
58. Goodenough, D.A.; Paul, D.L. Beyond the gap: Functions of unpaired connexon channels. Nat. Rev. Mol. Cell Biol., 2003, 4, 285-295.
59. Jiang, J.X.; Gu, S.; Gap junction-And hemichannel-independent actions of connexins. Biochem. Biophys. Acta Biomembr., 2005, 1711, 208-214. (Pubitemid 40799295)
60. Ivanov, D. V.; Tyazhelova, T. V.; Lemonnier, L.; Kononenko, N.; Pestova, A. A.; Nikitin, E. A.; Prevarskaya, N.; Skryma, R.; Panchin, Y. V.; Yankovsky, N. K.; Baranova, A. V. A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3. FEBS Lett., 2003, 539(1-3), 156-160. (Pubitemid 36351304)
61. Cho, Y. G.; Kim, C. J.; Song, J. H.; Rhie, D. J.; Park, Y. K.; Kim, S. Y.; Nam, S. W.; Yoo, N. J.; Lee, J. Y.; Park, W. S. Genetic and expression analysis of the KCNRG gene in hepatocellular carcinomas. Exp. Mol. Med., 2006, 38, 247-255.
62. Liu, Y.; Corcoran, M.; Rasool, O.; Ivanova, G.; Ibbotson, R.; Grandér, D.; Iyengar, A.; Baranova, A.; Kashuba, V.; Merup, M.; Wu, X.; Gardiner, A.; Mullenbach, R.; Poltaraus, A.; Hultström, A.L.; Juliusson, G.; Chapman, R.; Tiller, M.; Cotter, F.; Gahrton, G.; Yankovsky, N.; Zabarovsky, E.; Einhorn, S.; Oscier, D. Cloning of two candidate tumor suppressor genes within a 10 kb region on chromosome 13q14, frequently deleted in chronic lymphocytic leukaemia. Oncogene, 1997, 15(20), 2463-2473. (Pubitemid 27503532)
63. Dohner, H.; Stilgenbauer, S.; Dohner, K.; Bentz, M.; Lichter, P. Chromosome aberrations in B-cell chronic lymphocytic leukaemia: Reassessment based on molecular cytogenetic analysis. J. Mol. Med., 1999, 77(2), 266-281. (Pubitemid 29146578)
64. Rosenwald, A.; Ott, G.; Krumdiek, A.K.; Dreyling, M.H.; Katzenberger, T.; Kalla, J.; Roth, S; Ott, M.M.; Müller-Hermelink, H.K. A biological role for deletions in chromosomal band 13q14 in mantle cell and peripheral t-cell lymphomas? Genes Chromosomes Cancer, 1999, 26(3), 210-214. (Pubitemid 29468340)
65. Harrison, C.J.; Mazzullo, H.; Cheung, K.L.; Gerrard, G.; Jalali, G.R.; Mehta, A.; Osier, D.G.; Orchard, K.H. Cytogenetics of multiple myeloma: Interpretation of fluorescence in situ hybridization results. Br. J. Haematol., 2003, 120, 944-952. (Pubitemid 36411552)
66. Elnenaei, M.O.; Hamoudi, R.A.; Swansbury, J.; Gruszka-Westwood, A.M.; Brito-Babapulle, V.; Matutes, E.; Catovsky, D. Delineation of the minimal region of loss at 13q14 in multiple myeloma. Genes Chromosomes Cancer, 2003, 36, 99-106. (Pubitemid 36077386)
67. Cuddapah, V.A.; Sontheimer, H. Ion Channels and the Control of Cancer Cell Migration. Am. J. Physiol. Cell. Physiol., 2011, May 2004.
68. Juliano, R.L. Signal transduction by cell adhesion receptors and the cytoskeleton: Functions of integrins, cadherins, selectins, and immunoglobulin-superfamily members. Annu. Rev. Pharmacol. Toxicol., 2002, 42, 283-323. (Pubitemid 34160528)
69. Arcangeli, A. Ion Channels in the Tumor Cell-Microenvironment Cross Talk. Am. J. Physiol. Cell Physiol., 2011, May 11.
70. Becchetti, A; Arcangeli, A. Integrins and ion channels in cell migration: Implications for neuronal development, wound healing and metastatic spread. Adv. Exp. Med. Biol., 2010, 674, 107-123.
71. Giancotti, F.G.; Tarone, G. Positional control of cell fate through joint integrin/receptor protein kinase signaling. Annu. Rev. Cell Dev. Biol., 2003, 19, 173-206. (Pubitemid 37487347)
72. Qi, M.; Elion, E.A. MAP kinase pathways. J. Cell Sci., 2005, 118, 3569-3572. (Pubitemid 41309404)
73. Guo, T. B.; Lu, J.; Li, T.; Lu, Z.; Xu, G.; Xu, M.; Lu, L.; Dai, W. Insulinactivated, K+-channel-sensitive Akt pathway is primary mediator of ML-1 cell proliferation. Am. J. Physiol. Cell Physiol., 2005, 289, C257-263. (Pubitemid 41008872)
74. Brown, E. J. Integrin-Associated proteins. Curr. Opin. Cell Biol., 2002, 14, 603-607. (Pubitemid 35247744)
75. Levite, M.; Cahalon, L.; Peretz, A.; Hershkoviz, R.; Sobko, A.; Ariel, A.; Desai, R.; Attali, B.; Lider, O. Extracellular K+ and opening of voltage-gated potassium channels activate T cell integrin function: Physical and functional association between Kv1.3 channels and beta1 integrins. J. Exp. Med., 2000, 191, 1167-1176. (Pubitemid 30207679)
76. Artym, V.V.; Petty, H.R. Molecular proximity of Kv 1.3 voltage-gated potassium channels and beta(1)-integrins on the plasma membrane of melanoma cells: Effects of cell adherence and channel blockers. J. Gen. Physiol., 2002, 120, 29-37. (Pubitemid 34755774)
77. Cherubini, A.; Hofmann, G.; Pillozzi, S.; Guasti, L.; Crociani, O.; Cilia, E.; Di Stefano, P.; Degani, S.; Balzi, M.; Olivotto, M.; Wanke, E.; Becchetti, A.; Defilippi, P.; Wymore, R.; Arcangeli, A. Human ether-A-go-go-related gene 1 channels are physically linked to beta1 integrins and modulate adhesiondependent signaling. Mol. Biol. Cell, 2005, 16, 2972-2983. (Pubitemid 40741240)
78. Pillozzi, S.; Masselli, M.; De Lorenzo, E.; Accordi, B.; Cilia, E.; Crociani, O.; Amedei, A.; Veltroni, M.; D'Amico, M.; Basso, G.; Becchetti, A.; Campana, D.; Arcangeli, A. Chemotherapy resistance in acute lymphoblastic leukemia requires hERG1 channels and is overcome by hERG1 blockers. Blood, 2011, 117, 902-914.
79. de Jonge, H.J.; Huls, G.; de Bont, E.S. Gene expression profiling in acute myeloid leukaemia. Neth. J. Med., 2011, 69, 167-176.
80. Wouters, B.J.; Lowenberg, B.; Delwel, R. A decade of genome-wide gene expression profiling in acute myeloid leukemia: Flashback and prospects. Blood, 2009, 113, 291-298.
81. Doyle, D.A.; Morais Cabral, J.; Pfuetzner, R.A.; Kuo, A.; Gulbis, J.M.; Cohen, S.L.; Chait, B. T.; MacKinnon, R. The structure of the potassium channel: Molecular basis of K+ conduction and selectivity. Science, 1998, 280, 69-77. (Pubitemid 28169082)
82. Dutzler, R.; Campbell, E. B.; Cadene, M.; Chait, B. T.; MacKinnon, R. X-ray structure of a ClC chloride channel at 3.0 A reveals the molecular basis of anion selectivity. Nature, 2002, 415, 287-294. (Pubitemid 34087544)
83. Andersen, O. S. Perspectives on how to drug an ion channel. J. Gen. Physiol., 2008, 131, 395-397. (Pubitemid 351620095)
84. Shao, X.; Wu, K.; Hao, Z.; Hong, L.; Zhang, J.; Fan, D. The potent inhibitory effects of cisapride, a specific blocker for human ether-A-go-go-related gene (HERG) channel, on gastric cancer cells. Cancer Biol. Ther., 2005, 4, 295-301. (Pubitemid 41351289)
85. Shao, X.; Wu, K.; Guo, X.; Xie, M.; Zhang, J.; Fan, D. Expression and significance of HERG protein in gastric cancer. Cancer Biol. Ther., 2008, 7, 45-50. (Pubitemid 351590451)
86. Lastraioli, E.; Guasti, L.; Crociani, O.; Polvani, S.; Hofmann, G.; Witchel, H.; Bencini, L.; Calistri, M.; Messerini, L.; Scatizzi, M.; Moretti, R.; Wanke, E.; Olivotto, M.; Mugnai, G.; Arcangeli, A. herg1 gene and HERG1 protein are overexpressed in colorectal cancers and regulate cell invasion of tumor cells. Cancer Res., 2004, 64, 606-611. (Pubitemid 38120900)
87. Masi, A.; Becchetti, A.; Restano-Cassulini, R.; Polvani, S.; Hofmann, G.; Buccoliero, A. M.; Paglierani, M.; Pollo, B.; Taddei, G. L.; Gallina, P.; Di Lorenzo, N.; Franceschetti, S.; Wanke, E.; Arcangeli, A. hERG1 channels are overexpressed in glioblastoma multiforme and modulate VEGF secretion in glioblastoma cell lines. Br. J. Cancer, 2005, 93, 781-792 (Pubitemid 41486438)
88. Witchel, H. J.; Hancox, J. C. Familial and acquired long qt syn-drome and the cardiac rapid delayed rectifier potassium current. Clin. Exp. Pharmacol. Physiol., 2000, 27, 753-766.
89. Raschi, E.; Vasina, V.; Poluzzi, E.; De Ponti, F. The hERG K+ channel: Target and antitarget strategies in drug development. Pharmacol. Res., 2008, 57, 181-195.
90. Shah, R. R. Drug-induced QT interval prolongation-regulatory guidance and perspectives on hERG channel studies. Novartis Found. Symp., 2005, 266, 251-280.
91. De Ponti, F.; Poluzzi, E.; Montanaro, N. QT-interval prolongation by noncardiac drugs: Lessons to be learned from recent experience. Eur. J. Clin. Pharmacol., 2000, 56, 1-18. (Pubitemid 30317776)
92. Mitcheson, J.S. hERG potassium channels and the structural basis of druginduced arrhythmias. Chem. Res. Toxicol., 2008, 21,1005-1010.
93. Arcangeli, A.; Becchetti, A. New Trends in Cancer Therapy: Targeting Ion Channels and Transporters. Pharmaceuticals, 2010, 3(4), 1202-1224.
94. Kaczorowski, G.J.; McManus, O.B.; Priest, B.T.; Garcia, M.L. Ion channels as drug targets: The next GPCRs. J. Gen. Physiol., 2008, 131, 399-405. (Pubitemid 351620096)
95. Milnes, J.T.; Dempsey, C.E.; Ridley, J.M.; Crociani, O.; Arcangeli, A.; Hancox, J.C.; Witchel, H.J. Preferential closed channel blockade of HERG potassium currents by chemically synthesised BeKm-1 scorpion toxin. FEBS Lett., 2003, 547, 20-26. (Pubitemid 36829372)
96. Zhang, M.; Korolkova, Y.V.; Liu, J.; Jiang, M.; Grishin, E.V.; Tseng, G.N. BeKm-1 is a HERG-specific toxin that shares the structure with ChTx but the mechanism of action with ErgTx1. Biophys. J., 2003, 84, 3022-3036. (Pubitemid 36534464)
97. Restano-Cassulini, R.; Korolkova, Y.V.; Diochot, S.; Gurrola, G.; Guasti, L.; Possani, L.D.; Lazdunski, M.; Grishin, E.V.; Arcangeli, A.; Wanke, E. Species diversity and peptide toxins blocking selec-tivity of ether-A-go-gorelated gene subfamily K+ channels in the central nervous system. Mol. Pharmacol., 2006, 69, 1673-1683.
98. Zhang, M.; Liu, X.S.; Diochot, S.; Lazdunski, M.; Tseng, G.N. APETx1 from sea anemone Anthopleura elegantissima is a gating modifier peptide toxin of the human ether-A-go-go-related potassium channel. Mol. Pharmacol., 2007, 72, 259-268. (Pubitemid 47124106)
99. Ganapathi, S.B.; Kester, M.; Elmslie, K.S. State-dependent block of HERG potassium channels by R-roscovitine: Implications for cancer therapy. Am. J. Physiol. Cell Physiol., 2009, 296(4), 701-710.
100. Beeton, C.; Wulff, H.; Standifer, N. E.; Azam, P.; Mullen, K. M.; Pennington, M. W.; Kolski-Andreaco, A.; Wei, E.; Grino, A.; Counts, D. R.; Wang, P. H.; LeeHealey, C. J.; S Andrews, B.; Sankaranarayanan, A.; Homerick, D.; Roeck, W. W.; Tehranzadeh, J.; Stanhope, K. L.; Zimin, P.; Havel, P. J.; Griffey, S.; Knaus, H.; Nepom, G. T.; Gutman, G. A.; Calabresi, P. A.; Chandy, K. G. Kv1.3 channels are a therapeutic target for T cellmediated auto-immune diseases. Proc. Natl. Acad. Sci. USA, 2006, 103, 17414-17419. (Pubitemid 44788983)
101. Panyi, G.; Possani, L. D.; Rodri̧guez de la Vega, R. C.; Ga̧spa̧r, R.; Varga, Z. K+ channel blockers: Novel tools to inhibit T cell activa-tion leading to specific immunosuppression. Curr. Pharm. Des., 2006, 12, 2199-2220. (Pubitemid 43891395)
102. Wulff, H.; Pennington, M. Targeting effector memory T-cells with Kv1.3 blockers. Curr. Opin. Drug Discov. Devel., 2007, 10, 438-445. (Pubitemid 47093127)
103. Beeton, C.; Smith, B. J.; Sabo, J. K.; Crossley, G.; Nugent, D.; Khaytin, I.; Chi, V.; Chandy, K. G.; Pennington, M. W.; Norton, R. S. The Ddiastereomer of ShK toxin selectively blocks voltage-gated K+ channels and inhibits T lymphocyte proliferation. J. Biol. Chem., 2008, 283, 988-997.
104. Pagès, F.; Berger, A.; Camus, M.; Sanchez-Cabo, F.; Costes, A.; Molidor, R.; Mlecnik, B.; Kirilovsky, A.; Nilsson, M.; Damotte, D.; Meatchi, T.; Bruneval, P.; Cugnenc, P.H.; Trajanoski, Z.; Fridman, W.H.; Galon, J. Effector memory T cells, early metasta-sis, and survival in colorectal cancer. N. Engl. J. Med., 2005, 353, 2654-2666. (Pubitemid 41817714)
105. Galon, J.; Costes, A.; Sanchez-Cabo, F.; Kirilovsky, A.; Mlecnik, B.; Lagorce-Pagès, C.; Tosolini, M.; Camus, M.; Berger, A.; Wind, P.; Zinzindohouè, F.; Bruneval, P.; Cugnenc, P.H.; Trajanoski, Z.; Fridman, W.H.; Pagès F. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science, 2006, 313, 1960-1964. (Pubitemid 44498003)
106. Klebanoff, C.A.; Gattinoni, L.; Torabi-Parizi, P.; Kerstann, K.; Cardones, A.R.; Finkelstein, S.E.; Palmer, D.C.; Antony, P.A.; Hwang, S.T.; Rosenberg, S.A.; Waldmann, T.A., Restifo, N.P. Central memory self/tumorreactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. Proc. Natl. Acad. Sci. USA, 2005, 102, 9571-9576. (Pubitemid 40981722)
107. Rampe, D.; Murawsky, M.K.; Gran, J.; Lewis, E.W. The antipsychotic agent sertindole is a high affinity antagonist of the human cardiac potassium channel HERG. J. Pharmacol. Exp. Ther., 1998, 286, 788-793. (Pubitemid 29003470)
108. Anderson, J. D.; Hansen, T. P.; Lenkowski, P. W.; Walls, A. M.; Choudhury, I. M.; Schenck, H. A.; Friehling, M.; Holl, G. M.; Patel, M. K.; Sikes, R. A.; Brown, M. L. Voltage-gated sodium channel blockers as cytostatic inhibitors of the androgen-independent prostate cancer cell line PC-3. Mol. Cancer Ther., 2003, 2, 1149-1154.
109. Brown, M. L.; Zha, C. C.; Van Dyke, C. C.; Brown, G. B.; Brouillette, W. J. Comparative molecular field analysis of hydantoin binding to the neuronal voltage-dependent sodium channel. J. Med. Chem., 1999, 42, 1537-1545. (Pubitemid 29226725)
110. Sikes, R. A.; Walls, A. M.; Brennen, W. N.; Anderson, J. D.; Choudhury-Mukherjee, I.; Schenck, H. A.; Brown, M. L. Therapeutic approaches targeting prostate cancer progression using novel voltage-gated ion channel blockers. Clin. Prostate Cancer, 2003, 2, 181-187. (Pubitemid 38044667)
111. Yamamura, H.; Ugawa, S.; Ueda, T.; Morita, A.; Shoichi, S. TRPM8 activation suppresses cellular viability in human melanoma. Am. J. Physiol. Cell Physiol., 2008, 295, C296-301. (Pubitemid 352755761)
112. Bodding, M.; Wissenbach, U.; Flockerzi, V. Characterisation of TRPM8 as a pharmacophore receptor. Cell Calcium, 2007, 42, 618-628. (Pubitemid 47471362)
113. Gómez-Varela, D.; Zwick-Wallasch, E.; Knotgen, H.; Sa̧nchez, A.; Hettmann, T.; Ossipov, D.; Weseloh, R.; Contreras-Jurado, C.; Rothe, M.; Stuhmer, W.; Pardo, L.A. Monoclonal antibody blockade of the human Eag1 potassium channel function exerts antitu-mor activity. Cancer Res., 2007, 67, 7343-7349. (Pubitemid 47206564)
114. Zhou, W.; Cayabyab, F. S.; Pennefather, P. S.; Schlichter, L. C.; DeCoursey, T. E. HERG-like K+ channels in microglia. J. Gen. Physiol., 1998, 111, 781-794.
115. Klionsky, L.; Tamir, R.; Holzinger, B.; Bi, X.; Talvenheimo, J.; Kim, H.; Martin, F.; Louis, J.C.; Treanor, J.J.; Gavva, N.R. A polyclonal antibody to the prepore loop of transient receptor potential vanilloid type 1 blocks channel activation. J. Pharmacol. Exp. Ther., 2006, 319, 192-198. (Pubitemid 44455123)
116. Xu, S.Z.; Zeng, F.; Lei, M.; Li, J.; Gao, B.; Xiong, C.; Sivaprasadarao, A.; Beech, D.J. Generation of functional ion channel tools by E3 targeting. Nat. Biotechnol., 2005, 23, 1289-1293. (Pubitemid 41486857)
117. Martial, S.; Giorgelli, J-L.; Renaudo, A.; Derijard, B.; Soriani, O. SP600125 inhibits Kv channels through a JNK-independent pathway in cancer cells. Biochem. Biophys. Res. Commun., 2008, 366, 944-950.
118. Wang, J.; Xu, Y.Y.; Gongora, R.; Warnock, D.G.; Ma, H.P. An intermediateconductance Ca2+-Activated K+ channel mediates B lymphoma cell cycle progression induced by serum. Pflugers Arch., 2007, 454, 945-956. (Pubitemid 47338459)
119. Suh, K. S.; Mutoh, M.; Gerdes, M.; Yuspa, S. H. CLIC4, an intracellular chloride channel protein, is a novel molecular target for cancer therapy. J. Investig. Dermatol. Symp. Proc., 2005, 10, 105-109.
120. Hinman, L.M.; Hannann, P.R.; Wallace, R.; Menendez, A.T.; Durr, M.E.; Upeslacis, J. Preparation and characterization of monoclonal antibody conjugates of the calicheamicins: A novel and potent family of antitumor antibiotics. Cancer Res., 1993, 53, 3336-3342. (Pubitemid 23223306)
121. Singh, Y.; Palombo, M.; Sinko, P.J. Recent trends in targeted anticancer prodrug and conjugate design. Curr. Med. Chem., 2008, 15, 1802-1826.
122. Deshane, J.; Garner, C.C.; Sontheimer, H. Chlorotoxin inhibits glioma cell invasion via matrix metalloproteinase-2. J.Biol. Chem., 2003, 278, 4135-4144. (Pubitemid 36801150)
123. Mamelak, A. N.; Rosenfeld, S.; Bucholz, R.; Raubitschek, A.; Nabors, L. B.; Fiveash, J. B.; Shen, S.; Khazaeli, M. B.; Colcher, D.; Liu, A.; Osman, M.; Guthrie, B.; Schade-Bijur, S.; Hablitz, D. M.; Alvarez, V. L.; Gonda, M. A. Phase I single-dose study of intracavitary-Administered iodine-131-TM-601 in adults with recurrent high-grade glioma. J. Clin. Oncol., 2006, 24, 3644-3650. (Pubitemid 46630539)
124. Arcangeli, A.; Becchetti, A. Integrin structure and functional relation with ion channels. Adv. Exp. Med. Biol., 2010, 674, 1-7.
125. Ziegler, A. Thermodynamic studies and binding mechanisms of cellpenetrating peptides with lipids and glycosaminoglycans. Adv. Drug Deliv. Rev., 2008, 60, 580-597. (Pubitemid 351215575)
126. Segal, D.M.; Bast, B.J. Production of bispecific antibodies. In: Curr. Protoc. Immunol, 2001, Chap 2: Unit 2.13.
127. Mijatovic, T.; Van Quaquebeke, E.; Delest, B.; Debeir, O.; Darro, F.; Kiss, R. Cardiotonic steroids on the road to anti-cancer therapy. Biochim. Biophys. Acta, 2007, 1776, 32-57. (Pubitemid 47334788)
128. DeFelice, L.J.; Goswami, T. Transporters as channels. Annu. Rev. Physiol., 2007, 69, 87-112. (Pubitemid 46457637)
129. Chen, T.Y.; Hwang, T.C. CLC-0 and CFTR: Chloride channels evolved from transporters. Physiol. Rev., 2008, 88, 351-387.
130. Downing, J.R. Targeted therapy in leukemia. Mod. Pathol., 2008, 21(S2), 2-7.
131. Plosker, G.L.; Figgitt, D.P. Rituximab: A review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia. Drugs, 2003, 63(8), 803-843 (Pubitemid 36432084)
132. Perentesis, J.P.; Sievers, E.L. Targeted therapies for high-risk acute myeloid leukemia. Hematol. Oncol. Clin. North. Am., 2001, 15(4), 677-701. (Pubitemid 32959255)
133. Al-Kali, A.; Cortes, J.; Faderl, S.; Jones, D.; Abril, C.; Pierce, S.; Brandt, M.; Kantarjian, H.; Ravandi, F. Patterns of molecular response to and relapse after combination of sorafenib, idarubicin, and cytarabine in patients with FLT3 mutant acute myeloid leukemia. Clin. Lymphoma Myeloma Leuk., 2011, 11(4):361-366.
134. Prebet, T.; Vey, N. Vorinostat in acute myeloid leukemia and myelodysplastic syndromes. Expert. Opin. Investig. Drugs, 2011, 20(2), 287-295.
135. Garcia-Manero, G.; Assouline, S.; Cortes, J.; Estrov, Z.; Kantarjian, H.; Yang, H.; Newsome, W.M, Miller WH Jr, Rousseau C, Kalita A, Bonfils C, Dubay M, Patterson TA, Li Z, Besterman JM, Reid G, Laille E, Martell RE, Minden M. Phase 1 study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukemia. Blood, 2008, 112(4), 981-989.
136. Kadia, T.M.; Yang, H.; Ferrajoli, A.; Maddipotti, S.; Schroeder, C.; Madden, T.L., Holleran, J.L.; Egorin, M.J.; Ravandi, F.; Thomas, D.A.; Newsome, W.; Sanchez-Gonzalez, B.; Zwiebel, J.A.; Espinoza-Delgado, I.; Kantarjian, H.M.; Garcia-Manero G. A phase I study of vorinostat in combination with idarubicin in relapsed or refractory leukaemia. Br J Haematol., 2010, 150(1), 72-82.
137. Shimizu, S.; Narita, M.; Tsujimoto, Y. Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature,
138. Abu-Hamad, S.; Arbel, N.; Calo, D.; Arzoine, L.; Israelson, A.; Keinan. N.; Ben-Romano, R.; Friedman, O.; Shoshan-Barmatz, V. The VDAC1 Nterminus is essential both for apoptosis and the protective effect of antiapoptotic proteins. J. Cell Sci., 2009, 122, 1906-1916.
139. Zheng, Y.; Shi, Y.; Tian, C.; Jiang, C.; Jin, H.; Chen, J.; Almasan, A.; Tang, H.; Chen, Q. Essential role of the voltage-dependent anion channel (VDAC) in mitochondrial permeability transition pore opening and cytochrome c release induced by arsenic trioxide. Oncogene., 2004, 23(6), 1239-1247. (Pubitemid 38297178)
140. Bhattacharjee, H.; Carbrey, J.; Rosen, B.P.; Mukhopadhyay, R. Drug uptake and pharmacological modulation of drug sensitivity in leukemia by AQP9. Biochem. Biophys. Res. Commun., 2004, 322(3), 836-841. (Pubitemid 39164428)
141. Leung, J.; Pang, A.; Yuen, W.H.; Kwong, Y.L.; Tse, E.W. Relationship of expression of aquaglyceroporin 9 with arsenic uptake and sensitivity in leukemia cells. Blood, 2007, 109(2):740-746. (Pubitemid 46105976)
142. Liu, Z.; Shen, J.; Carbrey, J.M.; Mukhopadhyay, R.; Agre, P.; Rosen, B.P. Arsenite transport by mammalian aquaglyceroporins AQP7 and AQP9. Proc. Natl. Acad. Sci. USA, 2002, 99(9), 6053-6058. (Pubitemid 34493263)
143. Jamieson, C.; Moir, E.M.; Rankovic, Z.; Wishart, G. Medicinal chemistry of hERG optimizations: Highlights and hang-ups. J. Med. Chem., 2006, 49(17), 5029-5046. (Pubitemid 44260200)