Persistent current blockers of voltage-gated sodium channels: A clinical opportunity for controlling metastatic disease

Recent Patents on Anti-Cancer Drug Discovery

Volumn 8, Issue 1, 2013, Pages 66-84

  Djamgoz, Mustafa B A ^a,b   Onkal, Rustem ^a,b  

^a IMPERIAL COLLEGE LONDON   (United Kingdom)

^b CYPRUS INTERNATIONAL UNIVERSITY   (Turkey)

Author keywords

Hypoxia; Metastasis; Persistent current; Ranolazine; Riluzole; Voltage gated sodium channel

Indexed keywords

CARDIAC GLYCOSIDE; DRONEDARONE; LOCAL ANESTHETIC AGENT; MESSENGER RNA; NERAMEXANE; NUTRACEUTICAL; PLATINUM COMPLEX; RANOLAZINE; RILUZOLE; SODIUM CHANNEL NAV1.5; SODIUM CHANNEL NAV1.6; SODIUM CHANNEL NAV1.7; TAXANE DERIVATIVE; TETRODOTOXIN; VOLTAGE GATED SODIUM CHANNEL; VOLTAGE GATED SODIUM CHANNEL BLOCKING AGENT;

AMYOTROPHIC LATERAL SCLEROSIS; ANGINA PECTORIS; APOPTOSIS; BRAIN METASTASIS; BREAST CANCER; CANCER DIAGNOSIS; CANCER INHIBITION; CANCER THERAPY; CELL INVASION; DRUG BLOOD LEVEL; GENE SILENCING; GENETIC TRANSFECTION; HEART ARRHYTHMIA; HEART ATRIUM FIBRILLATION; HUMAN; HYPOXIA; IMMUNOHISTOCHEMISTRY; LUNG METASTASIS; MELANOMA; METASTASIS; METASTASIS INHIBITION; MULTIPLE SCLEROSIS; NERVE INJURY; NEUROLOGIC DISEASE; NEUROPATHIC PAIN; NOCICEPTIVE PAIN; NONHUMAN; OXIDATIVE STRESS; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN STRUCTURE; PULMONARY HYPERTENSION; RECOMMENDED DRUG DOSE; REVIEW; SODIUM CURRENT; SODIUM TRANSPORT; TUMOR MICROENVIRONMENT; TUMOR VASCULARIZATION; UPREGULATION;

EID: 84875466657     PISSN: 15748928     EISSN: None     Source Type: Journal    
DOI: 10.2174/1574892811308010066     Document Type: Review

References (260)

1. Wong SY, Hynes RO. Lymphatic or hematogenous dissemination: How does a metastatic tumour cell decide? Cell Cycle 2006; 5: 812-817.
2. Fidler IJ. Critical determinants of metastasis. Semin Cancer Biol 2002; 12: 89-96.
3. Fidler IJ. The organ microenvironment and cancer metastasis. Differentiation 2002; 70: 498-505.
4. Fidler IJ. The pathogenesis of cancer metastasis: The 'seed and soil' hypothesis revisited. Nat Rev Cancer 2003; 3: 453-458.
5. Hunter KW. Host genetics and tumour metastasis. Br J Cancer 2004; 90: 752-755.
6. Bacac M, Stamenkovic I. Metastatic cancer cell. Annu Rev Pathol 2007; 3: 221-247.
7. Hunter KW, Crawford NP, Alsarraj J. Mechanisms of metastasis. Breast Cancer Res 2008; 10: 1: S2.
8. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57-70.
9. Welch DR, Steeg PS, Rinker-Schaeffer CW. Molecular biology of breast cancer metastasis. Genetic regulation of human breast carcinoma metastasis. Breast Cancer Res 2000; 2: 408-416.
10. Welch DR. Microarrays bring new insights into understanding of breast cancer metastasis to bone. Breast Cancer Res 2004; 6: 61-4.
11. Welch DR. Do we need to redefine a cancer metastasis and staging definitions? Breast Dis 2006; 26: 3-12.
12. Berger JC, Vander-Griend D, Stadler WM, Rinker-Schaeffer C. Metastasis suppressor genes: Signal transduction, cross-talk and the potential for modulating the behavior of metastatic cells. Antican-cer Drugs 2004; 15: 559-568.
13. Weigelt B, Hu Z, He X, Livasy C, Carey LA, Ewend MG, et al. Molecular portraits and 70-gene prognosis signature are preserved throughout the metastatic process of breast cancer. Cancer Res 2005; 65: 9155-9158.
14. Vaidya KS, Welch DR. Metastasis suppressors and their roles in breast carcinoma. J Mammary Gland Biol Neoplasia 2007; 12: 175-190.
15. + current in the Mat-LyLu cell line of rat prostate cancer. Int J Biochem Cell Biol 2004; 36: 1249-1260.
16. Pan H, Djamgoz MBA. Biochemical constitution of extracellular medium is critical for control of human breast cancer MDA-MB-231 cell motility. J Membr Biol 2008; 223: 27-36.
17. Pietras K, Ostman A. Hallmarks of cancer: Interactions with the tumour stroma. Exp Cell Res 2010; 316: 1324-1331.
18. Spano D, Zollo M. Tumour microenvironment: A main actor in the metastasis process. Clin Exp Metastasis 2012; 29: 381-395.
19. Briest F, Berndt A, Clement J, Junker K, Eggeling FV, Grimm S, et al. Tumour-stroma interactions in tumourigenesis: Lessons from stem cell biology. Front Biosci 2012; 4: 1871-1887.
20. Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell 2011; 144: 646-674.
21. Linn MM, Ball RA, Maradiegue A. Prostate-specific antigen screening: Friend or foe? Urol Nurs 2007; 27: 481-489.
22. Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 2012; 486: 346-352.
23. Ghiaur G, Gerber J, Jones RJ. Concise review: Cancer stem cells and minimal residual disease. Stem Cells 2012; 30: 89-93.
24. Malik B, Nie D. Cancer stem cells and resistance to chemo and radio therapy. Front Biosci 2012; 4: 2142-2149.
25. McCarty MF. Current prospects for controlling cancer growth with non-cytotoxic agents-nutrients, phytochemicals, herbal extracts, and available drugs. Med Hypotheses 2001; 56: 137-154.
26. Khamly K, Jefford M, Michael M, Zalcberg J. Beyond 5-fluorouracil: New horizons in systemic therapy for advanced colorectal cancer. Expert Opin Investig Drugs 2005; 14: 607-628.
27. Martin L, Schilder RJ. Novel non-cytotoxic therapy in ovarian cancer: Current status and future prospects. J Natl Compr Canc Netw 2006; 4: 955-966.
28. Rosa DD, Ismael G, Lago LD, Awada A. Molecular-targeted therapies: Lessons from years of clinical development. Cancer Treat Rev 2008; 34: 61-80.
29. Fraser SP, Pardo LA. Ion channels: Functional expression and therapeutic potential in cancer. Colloquium on Ion Channels and Cancer. EMBO Rep 2008; 9: 512-515.
30. Prevarskaya N, Skryma R, Shuba Y. Ion channels and the hallmarks of cancer. Trends Mol Med 2010; 16: 107-121.
31. Catterall WA. From ionic currents to molecular mechanisms: The structure and function of voltage-gated sodium channels. Neuron 2000; 26: 13-25.
32. Catterall WA. Voltage-gated sodium channels at 60: Structure, function and pathophysiology. J Physiol 2012; 590: 2577-2589.
33. + channel p subunits in development and disease. Neurosci Lett 2010; 486: 53-539.
34. Brackenbury WJ, Isom LL. Na channel p subunits: Overachievers of the ion channel family. Front Pharmacol 2011; 2: 53.
35. Goldin AL. Resurgence of sodium channel research. Annu Rev Physiol 2001; 63: 871-894.
36. Yu FH, Catterall WA. Overview of the voltage-gated sodium channel family. Genome Biol 2003; 4: 207.
37. Swartz KJ. Sensing voltage across lipid membranes. Nature 2008; 456: 891-897.
38. Tombola F, Pathak MM, Isacoff EY. How does voltage open an ion channel? Annu Rev Cell Dev Biol 2006; 22: 23-52.
39. DeCaen PG, Yarov-Yarovoy V, Sharp EM, Scheuer T, Catterall WA. Sequential formation of ion pairs during activation of a sodium channel voltage sensor. Proc Natl Acad Sci USA 2009; 106: 22498-22503.
40. Abriel H, Kass RS. Regulation of the voltage-gated cardiac sodium channel Nav1.5 by interacting proteins. Trends Cardiovasc Med 2005; 15: 35-40.
41. Chahine M, Ziane R, Vijayaragavan K, Okamura Y. Regulation of Nav channels in sensory neurons. Trends Pharmacol Sci 2005; 26: 496-502.
42. Shao D, Okuse K, Djamgoz MBA. Protein-protein interactions involving voltage-gated sodium channels: Post-translational regulation, intracellular trafficking and functional expression. Int J Bio-chem Cell Biol 2009; 41: 1471-1481.
43. Goldin AL. Mechanisms of sodium channel inactivation. Curr Opin Neurobiol 2003; 13: 284-290.
44. + channels: Multiplicity of expression, plasticity, functional implications and pathophysiological aspects. Eur Biophys J 2004; 33: 180-193.
45. Catterall WA, Goldin AL, Waxman SG. International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol Rev 2005; 57: 397-409.
46. Rush AM, Cummins TR, Waxman SG. Multiple sodium channels and their roles in electrogenesis within dorsal root ganglion neurons. J Physiol 2007; 579: 1-14.
47. Fozzard HA, Lipkind GM. The tetrodotoxin binding site is within the outer vestibule of the sodium channel. Mar Drugs 2010; 8: 219-234.
48. Plummer NW, Meisler MH. Evolution and diversity of mammalian sodium channel genes. Genomics 1999; 57: 323-331.
49. Satin J, Kyle JW, Chen M, Bell P, Cribbs LL, Fozzard HA, et al. A mutant of TTX-resistant cardiac sodium channels with TTX-sensitive properties. Science 1992; 256: 1202-1205.
50. Heinemann SH, Terlau H, Stuhmer W, Imoto K, Numa S. Calcium channel characteristics conferred on the sodium channel by single mutations. Nature 1992; 356: 441-443.
51. Ju YK, Saint DA, Gage PW. Hypoxia increases persistent sodium current in rat ventricular myocytes. J Physiol 1996; 497: 337-347.
52. Saint DA. The cardiac persistent sodium current: An appealing therapeutic target? Br J Pharmacol 2008; 153: 1133-1142.
53. Zaza A, Belardinelli L, Shryock JC. Pathophysiology and pharmacology of the cardiac late sodium current. Pharmacol Ther 2008; 119: 326-339.
54. Kiss T. Persistent Na-channels: Origin and function. A review. Acta Biol Hung 2008; 59 (Suppl):1-12.
55. + channels in human prostate cancer cell lines and their contribution to invasion in vitro. Am J Pathol 1997; 150: 1213-1221.
56. Roger S, Besson P, Le Guennec JY. Involvement of a novel fast inward sodium current in the invasion capacity of a breast cancer cell line. Biochim Biophys Acta 2003; 1616: 107-111.
57. Fraser SP, Diss JKJ, Chioni AM, Mycielska ME, Pan H, Yamaci RF, et al. Voltage-gated sodium channel expression and potentia-tion of human breast cancer metastasis. Clin Cancer Res 2005; 11: 5381-5389.
58. Blandino JK, Viglione MP, Bradley WA, Oie HK, Kim YI. Voltage-dependent sodium channels in human small-cell lung cancer cells: Role in action potentials and inhibition by Lambert-Eaton syndrome IgG. J Membr Biol 1995; 143: 153-163.
59. + channel expression in vitro. J Membr Biol 2005; 204: 67-75.
60. Onganer PU, Seckl MJ, Djamgoz MBA. Neuronal characteristics of small-cell lung cancer. Br J Cancer 2005; 93: 1197-1201.
61. Roger S, Rollin J, Barascu A, Besson P, Raynal PI, Iochmann S, et al. Voltage-gated sodium channels potentiate the invasive capacities of human non-small-cell lung cancer cell lines. Int J Bio-chem Cell Biol 2007; 39: 774-786.
62. Fulgenzi G, Graciotti L, Faronato M, Soldovieri MV, Miceli F, Amoroso S, et al. Human neoplastic mesothelial cells express voltage-gated sodium channels involved in cell motility. Int J Biochem Cell Biol 2006; 38: 1146-1159.
63. + channels in human neuro-blastoma cells are encoded by new variants of Nav1.5/SCN5A. Eur J Neurosci 2005; 22: 793-801.
64. + channel activity. FEBS Lett 2004; 569: 191-194.
65. Allen DH, Lepple-Wienhues A, Cahalan MD. Ion channel pheno-type of melanoma cell lines. J Membr Biol 1997; 155: 27-34.
66. Diaz D, Delgadillo DM, Hernández-Gallegos E, Ramírez-Domínguez ME, Hinojosa LM, Ortiz CS, et al. Functional expression of voltage-gated sodium channels in primary cultures of human cervical cancer. J Cell Physiol 2007; 210: 469-478.
67. Hernandez-Plata E, Ortiz CS, Marquina-Castillo B, Medina-Martinez I, Alfaro A, Berumen J, et al. Overexpression of NaV1.6 channels is associated with the invasion capacity of human cervical cancer. Int J Cancer 2012; 130: 2013-2023.
68. Gao R, Shen Y, Cai J, Lei M, Wang Z. Expression of voltage-gated sodium channel alpha subunit in human ovarian cancer. Oncol Rep 2010; 23: 293-299.
69. + channel SCN5A is a key regulator of a gene transcriptional network that controls colon cancer invasion. Cancer Res 2010; 70: 6957-6967.
70. Brackenbury WJ, Chioni AM, Diss JKJ, Djamgoz MBA. The neonatal splice variant of Nav1.5 potentiates in vitro invasive behaviour of MDA-MB-231 human breast cancer cells. Breast Cancer Res Treat 2007; 101: 149-160.
71. Diss JKJ, Stewart D, Pani F, Foster CS, Walker MM, Patel A, et al. A potential novel marker for human prostate cancer: Voltage-gated sodium channel expression in vivo. Prostate Cancer Prostatic Dis 2005; 8: 266-273.
72. Nakajima T, Kubota N, Tsutsumi T, Oguri A, Imuta H, Jo T, et al. Eicosapentaenoic acid inhibits voltage-gated sodium channels and invasiveness in prostate cancer cells. Br J Pharmacol 2009; 56: 420-431.
73. Onkal R, Djamgoz MBA. Molecular pharmacology of voltage-gated sodium channel expression in metastatic disease: Clinical potential of neonatal Nav1.5 in breast cancer. Eur J Pharmacol 2009; 625: 206-219.
74. Maier SK, Westenbroek RE, McCormick KA, Curtis R, Scheuer T, Catterall WA. Distinct subcellular localization of different sodium channel alpha and beta subunits in single ventricular myocytes from mouse heart. Circulation 2004; 109: 1421-1427.
75. Maier SK, Westenbroek RE, Schenkman KA, Feigl EO, Scheuer T, Catterall WA. An unexpected role for brain-type sodium channels in coupling of cell surface depolarization to contraction in the heart. Proc Natl Acad Sci USA 2002; 99: 4073-4078.
76. + channels in the developing mouse heart. J Physiol 2005; 564: 683-696.
77. WJ. Voltage-gated sodium channels and metastatic disease. Channels (Austin) 2012; 6: (5).
78. + channels in human endothelial cells: Modulation of vascular endothelial growth factor (VEGF) signalling. J Biol Chem 2011; 286: 16846-16860.
79. Eccles SA. Parallels in invasion and angiogenesis provide pivotal points for therapeutic intervention. Int J Dev Biol 2004; 48: 583-598.
80. Sherman SJ, Catterall WA. Electrical activity and cytosolic calcium regulate levels of tetrodotoxin-sensitive sodium channels in cultured rat muscle cells. Proc Natl Acad Sci USA 1984; 81: 262-266.
81. + channels induced by phenytoin in brains of genetically seizure-susceptible (E1) and control (ddY) mice. Neurosci 1994; 62: 803-811.
82. + channel expression in Mat-LyLu rat prostate cancer cell line. J Physiol 2006; 573: 343-356.
83. Iwahashi Y, Furuyama T, Inagaki S, Morita Y, Takagi H. Distinct regulation of sodium channel types I, II and III following nerve transection. Mol Brain Res 1994: 22: 341-345.
84. Black JA, Waxman SG. Sodium channel expression: A dynamic process in neurons and non-neuronal cells. Dev Neurosci 1996; 18: 139-152.
85. Mao Q, Jia F, Zhang XH, Qiu YM, Ge JW, Bao WJ, et al. The up-regulation of voltage-gated sodium channel Nav1.6 expression following fluid percussion traumatic brain injury in rats. Neurosurg 2010; 66: 1134-1139.
86. + channels: Differential regulation in adult versus fetal rat brain. Neurosci 1999; 94: 1231-1243.
87. Xia Y, Fung ML, O'Reilly JP, Haddad GG. Increased neuronal excitability after long-term O(2) deprivation is mediated mainly by sodium channels. Brain Res Mol Brain Res 2000; 76: 211-219.
88. Caceres AI, Obeso A, Gonzalez C, Rocher A. Molecular identification and functional role of voltage-gated sodium channels in rat carotid body chemoreceptor cells. Regulation of expression by chronic hypoxia in vivo. J Neurochem 2007; 102: 231-245.
89. + channel activity and Transwell migration in Mat-LyLu rat prostate cancer cell line. J Cell Physiol 2007; 210: 602-608.
90. Toledo-Aral JJ, Brehm P, Halegoua S, Mandel GA. Single pulse of nerve growth factor triggers long-term neuronal excitability through sodium channel gene induction. Neuron 1995; 14: 607-611.
91. Uysal-Onganer P, Djamgoz MBA. Epidermal growth factor potentiates in vitro metastatic behaviour of human prostate cancer PC-3M cells: Involvement of voltage-gated sodium channel. Mol Cancer 2007; 6: 76.
92. + channel activity. J Cell Physiol 2008; 215: 77-81.
93. Vijayaragavan K, Boutjdir M, Chahine M. Modulation of Nav1.7 and Nav1.8 peripheral nerve sodium channels by protein kinase A and protein kinase C. J Neurophysiol 2004; 91: 1556-1569.
94. Chioni AM, Shao D, Grose R, Djamgoz MBA. Protein kinase A and regulation of neonatal Nav1.5 expression in human breast cancer cells: Activity-dependent positive feedback and cellular migration. Int J Biochem Cell Biol 2010; 42: 346-358.
95. Tabb JS, Fanger GR, Wilson EM, Maue RA, Henderson LP. Suppression of sodium channel function in differentiating C2 muscle cells stably overexpressing rat androgen receptors. J Neurosci 1994; 14: 763-773.
96. Zakon HH. The effects of steroid hormones on electrical activity of excitable cells. Trends Neurosci 1998; 21: 202-207.
97. Diss JKJ, Fraser SP, Walker MM, Patel A, Latchman DS, Djamgoz MBA. Beta-subunits of voltage-gated sodium channels in human prostate cancer: Quantitative in vitro and in vivo analyses of mRNA expression. Prostate Cancer Prostatic Dis 2008; 11: 325-333.
98. Fraser SP, Ozerlat-Gunduz I, Onkal R, Diss JKJ, Latchman DS, Djamgoz MBA. Estrogen and non-genomic upregulation of voltage-gated Na(+) channel activity in MDA-MB-231 human breast cancer cells: Role in adhesion. J Cell Physiol 2010; 224: 527-539.
99. Veronesi U, Boyle P, Goldhirsch A, Orecchia R, Viale G. Breast cancer. Lancet 2005; 365: 1727-1741.
100. + currents in two prostatic tumour cell lines: Contribution to inva-siveness in vitro. FEBS Letts 1995; 369: 290-294.
101. Smith P, Rhodes NP, Shortland AP, Fraser SP, Djamgoz MBA, Ke Y, et al. Sodium channel protein expression enhances the invasive-ness of rat and human prostate cancer cells. FEBS Lett 1998; 423: 19-24.
102. + channels confer invasive properties on human prostate cancer cells. Pflugers Arch 2004; 447: 908-914.
103. Gillet L, Roger S, Besson P, Lecaille F, Gore J, Bougnoux P, et al. Voltage-gated sodium channel activity promotes cysteine cathep-sin-dependent invasiveness and colony growth of human cancer cells. J Biol Chem 2009; 284: 8680-8691.
104. + channel 'neonatal' isoform. J Neurosci Methods 2005; 147: 88-98.
105. Fraser SP, Ding Y, Liu A, Foster CS, Djamgoz MBA. Tetrodotoxin suppresses morphological enhancement of the metastatic Mat-LyLu rat prostate cancer cell line. Cell Tissue Res 1999; 295: 505-512.
106. + channel expression to cell behaviors involved in the metastatic cascade in rat prostate cancer: I. lateral motility. J Cell Physiol 2003; 195: 479-487.
107. + channel activity. J Cell Sci 2001; 114: 2697-2705.
108. + channel expression. Eur Biophys J 2008; 37: 359-368.
109. + channel expression to cell behaviors involved in the metastatic cascade in rat prostate cancer: II. Secretory membrane activity. J Cell Physiol 2003; 195: 461-469.
110. + channel activity. J Physiol 2005; 563: 393-408.
111. + channel activity in rat prostate cancer cells: Fractal analyses. Eur Biophys J 2004; 33: 535-542.
112. Djamgoz MBA. In: Pullar C, Ed. The Physiology of Bioelectricity in Development, Tissue Regeneration, and Cancer. London and New York: Taylor & Francis 2011: 269-294.
113. Sikes RA, Walls AM, Brennen WN, Anderson JD, Choudhury-Mukherjee I, Schenck HA, et al. Therapeutic approaches targeting prostate cancer progression using novel voltage-gated ion channel blockers. Clin Prostate Cancer 2003; 2: 181-187.
114. Yang M, Kozminski DJ, Wold LA, Modak R, Calhoun JD, Isom LL, et al. Therapeutic potential for phenytoin: Targeting Na(v)1.5 sodium channels to reduce migration and invasion in metastatic breast cancer. Breast Cancer Res Treat 2012; 134(2): 603-615.
115. Isbilen B, Fraser SP, Djamgoz MBA. Docosahexaenoic acid (omega-3) blocks voltage-gated sodium channel activity and migration of MDA-MB-231 human breast cancer cells. Int J Biochem Cell Biol 2006; 38: 2173-2182.
116. Djamgoz MBA, Isbilen B. Dietary compounds as anti-cancer agents: A preliminary evaluation of ion channels and membrane excitability as possible target mechanisms. Turk J Biochem 2006; 31: 57-68.
117. Abdul M, Hoosein N. Voltage-gated sodium ion channels in prostate cancer: Expression and activity. Anticancer Res 2002; 22: 1727-1730.
118. + channel in human small-cell lung cancer: Control of proliferation in vitro and detection in vivo. J Physiol 2004; 565P: PC109.
119. Ouwerkerk R, Jacobs MA, Macura KJ, Wolff AC, Stearns V, Mez-ban SD, et al. Elevated tissue sodium concentration in malignant breast lesions detected with non-invasive 23Na MRI. Breast Cancer Res Treat 2007; 106: 151-160.
120. Henzler T, Konstandin S, Schmid-Bindert G, Apfaltrer P, Haneder S, Wenz F, et al. Imaging of tumour viability in lung cancer: Initial results using 23Na-MRI. Rofo 2012; 184: 340-344.
121. Babsky AM, Ju S, Bennett S, George B, McLennan G, Bansal N. Effect of implantation site and growth of hepatocellular carcinoma on apparent diffusion coefficient of water and sodium MRI. NMR Biomed 2012; 25: 312-321.
122. Yildirim S, Altun S, Gumushan H, Patel A, Djamgoz MBA. Voltage-gated sodium channel activity promotes prostate cancer metastasis in vivo. Cancer Lett 2012; 323: 58-61.
123. Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: How are they linked? Free Radic Biol Med 2010; 49: 1603-1616.
124. Kryston TB, Georgiev AB, Pissis P, Georgakilas AG. Role of oxi-dative stress and DNA damage in human carcinogenesis. Mutat Res 2011; 711: 193-201.
125. Jiang J, Tang YL, Liang XH. EMT: A new vision of hypoxia promoting cancer progression. Cancer Biol Ther 2011; 11: 714-723.
126. Noman MZ, Messai Y, Carré T, Akalay I, Méron M, Janji B, et al. Microenvironmental hypoxia orchestrating the cell stroma cross talk, tumour progression and antitumour response. Crit Rev Immunol 2011; 31: 357-377.
127. Ekberg J, Craik DJ, Adams DJ. Conotoxin modulation of voltage-gated sodium channels. Int J Biochem Cell Biol 2008; 40: 2363-2368.
128. Batcioglu K, Uyumlu AB, Satilmis B, Yildirim B, Yucel N, Demirtas H, et al. Oxidative stress in the in vivo DMBA rat model of breast cancer: Suppression by a voltage-gated sodium channel inhibitor (RS100642). Basic Clin Pharmacol Toxicol 2012; 111(2): 137-141.
129. Sheets, MF, Fozzard HA, Lipkind GM, Hanck DA. Sodium channel molecular conformations and antiarrhythmic drug affinity. Trends Cardiovasc Med 2010; 20: 16-21.
130. Mansell J, Monypenny IJ, Skene AI, Abram P, Carpenter R, Gat-tuso JM, et al. Patterns and predictors of early recurrence in postmenopausal women with estrogen-receptor positive early breast cancer. Breast Cancer Res Treat 2009; 117: 91-98.
131. Vigneault L, Turgeon AF, Côté D, Lauzier F, Zarychanski R, Moore L, et al. Perioperative intravenous lidocaine infusion for postoperative pain control: A meta-analysis of randomised controlled trials. Can J Anaesth 2011; 58: 22-37.
132. Brahimi-Horn MC, Pouysségur J. HIF at a glance. J Cell Sci 2009; 122: 1055-1057.
133. Lanzen J, Braun RD, Klitzman B, Brizel D, Secomb TW, Dewhirst MW. Direct demonstration of instabilities in oxygen concentrations within the extravascular compartment of an experimental tumour. Cancer Res 2006; 66: 2219-2223.
134. Vaupel P, Mayer A. Hypoxia in cancer: Significance and impact on clinical outcome. Cancer Metastasis Rev 2007; 26: 225-2239.
135. Bertout JA, Patel SA, Simon MC. The impact of O2 availability on human cancer. Nat Rev Cancer 2008; 8: 967-975.
136. Brahimi-Horn M, Pouysségur J. Harnessing the hypoxia-inducible factor in cancer and ischemic disease. Biochem Pharmacol 2007; 73: 450-457.
137. Brahimi-Horn M, Pouysségur J. Oxygen, a source of life and stress. FEBS Lett 2007; 581: 3582-3591.
138. Hoogsteen IJ, Lok J, Marres HAM, Takes RP, Rijken PFJW, van der Kogel AJ, et al. Hypoxia in larynx carcinomas assessed by pi-monidazole binding and the value of CA-IX and vascularity as surrogate markers of hypoxia. Eur J Cancer 2009; 45: 2906-29014.
139. Brizel DM, Scully SP, Harrelson JM, Layfield LJ, Dodge RK, Charles HC, et al. Radiation therapy and hyperthermia improve the oxygenation of human soft tissue sarcomas. Cancer Res 1996; 56: 5347-5350.
140. Brown NS, Bicknell R. Hypoxia and oxidative stress in breast cancer. Oxidative stress: Its effects on the growth, metastatic potential and response to therapy of breast cancer. Breast Cancer Res 2001; 3: 323-327.
141. Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2002; 2: 563-572.
142. Zhang L, Hill RP. Hypoxia enhances metastatic efficiency by up-regulating Mdm2 in KHT cells and increasing resistance to apoptosis. Cancer Res 2004; 64: 4180-4189.
143. Bristow RG, Hill RP. Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer 2008; 8: 180-192.
144. Subarsky P, Hill RP. Graded hypoxia modulates the invasive potential of HT1080 fibrosarcoma and MDA MB231 carcinoma cells. Clin Exp Metastasis 2008; 25: 253-264.
145. + channels and hypertrophy in chromaffin-like arterial chemoreceptors. Proc Natl Acad Sci USA 1992; 89: 9469-9473.
146. Stea A, Jackson A, Macintyre L, Nurse CA. Long-term modulation of inward currents in O2 chemoreceptors by chronic hypoxia and cyclic AMP in vitro. J Neurosci 1995; 15: 2192-2202.
147. Fearon IM, Brown ST. Acute and chronic hypoxic regulation of recombinant hNa(v)1.5 alpha subunits. Biochem Biophys Res Commun 2004; 324: 1289-1295.
148. Wang W, Ma J, Zhang P, Luo A. Redox reaction modulates transient and persistent sodium current during hypoxia in guinea pig ventricular myocytes. Pflugers Arch 2007; 454: 461-475.
149. Hammarström AK, Gage PW. Hypoxia and persistent sodium current. Eur Biophys J 2002; 31: 323-330.
150. Burnashev NA, Undrovinas AI, Fleidervish IA, Makielski JC, Rosenshtraukh LV. Modulation of cardiac sodium channel gating by lysophosphatidylcholine. J Mol Cell Cardiol 1991; 23: 23-30.
151. Wu J, Corr PB. Palmitoyl carnitine modifies sodium currents and induces transient inward current in ventricular myocytes. Am J Physiol 1994; 266: 1034-1046.
152. Song Y, Shryock JC, Wagner S, Maier LS, Belardinelli L. Blocking late sodium current reduces hydrogen peroxide-induced ar-rhythmogenic activity and contractile dysfunction. J Pharmacol Exp Ther 2006; 318: 214-222.
153. Schreibmayer W, Kazerani H, Tritthart HA. A mechanistic interpretation of the action of toxin II from Anemonia sulcata on the cardiac sodium channel. Biochim Biophys Acta 1987: 901; 273-282.
154. + channel mutation causing hyperkalemic periodic paralysis. Neuron 1993; 10: 667-678.
155. + current in rat hippocampal neurones via protein kinase C. J Physiol 1997; 503: 479-488.
156. Maltsev VA, Sabbah HN, Higgins RS, Silverman N, Lesch M, Undrovinas AI. Novel, ultraslow inactivating sodium current in human ventricular cardiomyocytes. Circulation 1998; 98: 2545-2552.
157. Hammarström AK, Gage PW. Oxygen-sensing persistent sodium channels in rat hippocampus. J Physiol 2000; 529: 107-118.
158. + current during cardiac ischemia and hypoxia. J Cardiovasc Electrophysiol 2006; 1: 96-103.
159. Belardinelli L, Shryock JC, Fraser H. Inhibition of the late sodium current as a potential cardioprotective principle: Effects of the late sodium current inhibitor ranolazine. Heart 2006; 92: iv6-iv14.
160. Haigney MC, Lakatta EG, Stern MD, Silverman HS. Sodium channel blockade reduces hypoxic sodium loading and sodium-dependent calcium loading. Circulation 1994; 90: 391-399.
161. Eigel BN, Hadley RW. Contribution of the Na(+) channel and Na(+)/H(+) exchanger to the anoxic rise of [Na(+)] in ventricular myocytes. Am J Physiol 1999; 277: 1817-1822.
162. Xiao XH, Allen DG. Role of Na(+)/H(+) exchanger during ischemia and preconditioning in the isolated rat heart. Circ Res 1999; 85: 723-730.
163. O'Rourke B, Maack C. The role of Na dysregulation in cardiac disease and how it impacts electrophysiology. Drug Discov Today Dis Models 2007; 4: 207-17.
164. Maltsev VA, Silverman N, Sabbah HN, Undrovinas AI. Chronic heart failure slows late sodium current in human and canine ventricular myocytes: Implications for repolarization variability. Eur J Heart Fail 2007; 9: 219-227.
165. Ward CA, Giles WR. Ionic mechanism of the effects of hydrogen peroxide in rat ventricular myocytes. J Physiol 1997; 500: 631-642.
166. Undrovinas AI, Maltsev VA, Sabbah HN. Repolarization abnormalities in cardiomyocytes of dogs with chronic heart failure: Role of sustained inward current. Cell Mol Life Sci 1999; 55: 494-505.
167. Tian XL, Yong SL, Wan X, Wu L, Chung MK, Tchou PJ, et al. Mechanisms by which SCN5A mutation N1325S causes cardiac arrhythmias and sudden death in vivo. Cardiovasc Res 2004; 61: 256-267.
168. 2+-exchanger in heart failure. Cardiovasc Res 2003; 57: 986-995.
169. +]i handling in the failing human heart. Cardiovasc Res 2003; 57: 874-886.
170. + in normal and failing cardiac myocytes. Ann NY Acad Sci 2006; 1080: 165-177.
171. Maltsev VA, Undrovinas A. Late sodium current in failing heart: Friend or foe? Prog Biophys Mol Biol 2008; 96: 421-451.
172. Hempleman SC. Sodium and potassium current in neonatal rat carotid body cells following chronic in vivo hypoxia. Brain Res 1995; 699: 42-50.
173. + channel mRNA subtypes in the developing rat cortex. Brain Res Mol Brain Res 2001; 91: 154-158.
174. Patlak JB, Ortiz M. Slow currents through single sodium channels of the adult rat heart. J Gen Physiol 1985; 86: 89-104.
175. Zilberter YI, Starmer CF, Starobin J, Grant AO. Late Na channels in cardiac cells: The physiological role of background Na channels. Biophys J 1994; 67: 153-160.
176. Maltsev VA, Kyle JW, Mishra S, Undrovinas A. Molecular identity of the late sodium current in adult dog cardiomyocytes identified by Nav1.5 antisense inhibition. Am J Physiol Heart Circ Physiol 2008; 295: H667-H676.
177. + channels from human atrium and ventricle. Circ Res 2002; 91: 421-426.
178. + channel in normal and failing human myocardium. J Mol Cell Cardiol 2002; 34: 1477-1489.
179. + current in human ventricular cardiomyocytes. Cardiovasc Res 2006; 69: 116-127.
180. Lu B, Su Y, Das S, Liu J, Xia J, Ren D. The neuronal channel NALCN contributes resting sodium permeability and is required for normal respiratory rhythm. Cell 2007; 129: 371-383.
181. Lu B, Su Y, Das S, Wang H, Wang Y, Liu J, et al. Peptide neuro-transmitters activate a cation channel complex of NALCN and UNC-80. Nature 2009; 457: 741-744.
182. Saint DA, Ju YK, Gage PW. A persistent sodium current in rat ventricular myocytes. J Physiol 1992; 453: 219-231.
183. + channel activity in dendritic processes of mammalian cortical neurones. J Physiol 1999; 521: 629-636.
184. Taddese A, Bean BP. Subthreshold sodium current from rapidly inactivating sodium channels drives spontaneous firing of tubero-mammillary neurons. Neuron 2002; 33: 587-600.
185. Crill WE. Persistent sodium current in mammalian central neurons. Annu Rev Physiol 1996; 58: 349-362.
186. Aman TK, Grieco-Calub TM, Chen C, Rusconi R, Slat EA, Isom LL, et al. Regulation of persistent Na current by interactions between beta subunits of voltage-gated Na channels. J Neurosci 2009; 29: 2027-2042.
187. Qu Y, Curtis R, Lawson D, Gilbride K, Ge P, DiStefano PS. Differential modulation of sodium channel gating and persistent sodium currents by the beta1, beta2, and beta3 subunits. Mol Cell Neurosci 2001; 18: 570-580.
188. Hammarström AK, Gage PW. Nitric oxide increases persistent sodium current in rat hippocampal neurons. J Physiol 1999; 520: 451-461.
189. Ahern GP, Hsu SF, Klyachko VA, Jackson MB. Induction of persistent sodium current by exogenous and endogenous nitric oxide. J Biol Chem 2000; 275: 28810-28815.
190. Shryock JC, Belardinelli L. Inhibition of late sodium current to reduce electrical and mechanical dysfunction of ischaemic myocardium. Br J Pharmacol 2008; 153: 1128-1132.
191. 2+ release in rat optic nerve during in vitro chemical ischemia. J Neurosci 2005; 25: 9960-9967.
192. Bennay M, Langer J, Meier SD, Kafitz KW, Rose CR. Sodium signals in cerebellar Purkinje neurons and Bergmann glial cells evoked by glutamatergic synaptic transmission. Glia 2008; 56: 1138-1149.
193. Medvedeva YV, Kim MS, Schnizler K, Usachev YM. Functional tetrodotoxin-resistant Na(+) channels are expressed presynaptically in rat dorsal root ganglia neurons. Neurosci 2009; 159: 559-569.
194. Spadoni F, Hainsworth AH, Mercuri NB, Caputi L, Martella G, Lavaroni F, et al. Lamotrigine derivatives and riluzole inhibit INa,P in cortical neurons. Neuroreport 2002; 13: 1167-1170.
195. Pignier C, Rougier J-S, Vie B, Culie C, Verscheure Y, Vacher B, et al. Selective inhibition of persistent sodium current by F 15845 prevents ischaemia-induced arrhythmias Br J Pharmacol 2010; 161: 79-91.
196. LS. A novel mechanism for the treatment of angina, arrhythmias, and diastolic dysfunction: Inhibition of late I-Na using ranolazine. J Cardiovasc Pharmacol 2009; 54: 279-286.
197. Kahlig KM, Lepist I, Leung K, Rajamani S, George AL. Rano-lazine selectively blocks persistent current evoked by epilepsy-associated Na(v)1.1 mutations. Br J Pharmacol 2010; 161: 1414-1426.
198. Urbani, A, Belluzzi O. Riluzole inhibits the persistent sodium current in mammalian CNS neurons. Eur J Neurosci 2000: 12: 3567-3574.
199. 2+ currents and modulates release of glutamate via presynaptic NMDA receptors on neonatal rat hypoglossal motoneurons in vitro. Eur J Neurosci 2008; 27: 2501-2514.
200. Weiss SM, Saint DA. The persistent sodium current blocker rilu-zole is antiarrhythmic and anti-ischaemic in a pig model of acute myocardial infarction. PLoS One 2010; 5: 14103.
201. Mycielska ME, Djamgoz MBA. Cellular mechanisms of direct-current electric field effects: Galvanotaxis and metastatic disease. J Cell Sci 2004; 117: 1631-1639.
202. Roger S, Potier M, Vandier C, Besson P, Le Guennec JY. Voltage-gated sodium channels: New targets in cancer therapy? Curr Pharm Des 2006; 12: 3681-3695.
203. Reddy R, Smith D, Wayman G, Wu Z, Villacres EC, Storm DR. Voltage-sensitive adenylyl cyclase activity in cultured neurons. A calcium-independent phenomenon. J Biol Chem 1995; 270: 14340-14346.
204. Cooper DM, Schell MJ, Thorn P, Irvine RF. Regulation of adenylyl cyclase by membrane potential. J Biol Chem 1998; 273: 27703-27707.
205. Murakami Y, Tanaka J, Koshimura K, Kato Y. Involvement of tetrodoxin-sensitive sodium channels in rat growth hormone secretion induced by pituitary adenylate cyclase-activating polypeptide (PACAP). Regul Pept 1998; 73: 119-121.
206. Yuhi T, Wada A, Kobayashi H, Yamamoto R, Yanagita T, Niina H. Up-regulation of functional voltage-dependent sodium channels by cyclic AMP-dependent protein kinase in adrenal medulla. Brain Res 1996; 709: 37-43.
207. Frohnwieser B, Chen LQ, Schreibmayer W, Kallen RG. Modulation of the human cardiac sodium channel alpha-subunit by cAMP-dependent protein kinase and the responsible sequence domain. J Physiol 1997; 498: 309-318.
208. Zhou J, Yi J, Hu N, George AL Jr, Murray KT. Activation of protein kinase A modulates trafficking of the human cardiac sodium channel in Xenopus oocytes. Circ Res 2000; 87: 33-38.
209. Zhou J, Shin HG, Yi J, Shen W, Williams CP, Murray KT. Phos-phorylation and putative ER retention signals are required for protein kinase A-mediated potentiation of cardiac sodium current. Circ Res 2002; 91: 540-546.
210. Ingwall JS. How high does intracellular sodium rise during acute myocardial ischaemia? A view from NMR spectroscopy. Cardio-vasc Res 1995; 29: 279.
211. E. Cardiac ionic currents and acute ischemia: From channels to arrhythmias. Physiol Rev 1999; 79: 917-1017.
212. Friedman JE, Haddad GG. Anoxia induces an increase in intracel-lular sodium in rat central neurons in vitro. Brain Res 1994; 663: 329-334.
213. McCormack JG, Baracos VE, Barr R, Lopaschuk GD. Effects of ranolazine on oxidative substrate preference in epitrochlearis muscle. J Appl Physiol 1996; 81: 905-910.
214. McCormack JG, Stanley WC, Wolff AA. Ranolazine: A novel metabolic modulator for the treatment of angina. Gen Pharmacol 1998; 30: 639-645.
215. Sabbah HN, Chandler MP, Mishima T, Suzuki G, Chaudhry P, Nass O, et al. Ranolazine, a partial fatty acid oxidation (pFOX) inhibitor, improves left ventricular function in dogs with chronic heart failure. J Card Fail 2002; 8: 416-422.
216. Fredj S, Sampson KJ, Liu H, Kass RS. Molecular basis of rano-lazine block of LQT-3 mutant sodium channels: Evidence for site of action. Br J Pharmacol 2006; 148: 16-24.
217. Antzelevitch C, Belardinelli L, Wu L, Fraser H, Zygmunt AC, Burashnikov A, et al. Electrophysiologic properties and antiar-rhythmic actions of a novel antianginal agent. J Cardiovasc Pharmacol Ther 2004; 9: S65-S83.
218. + channels. Br J Pharmacol 2003; 140: 881-888.
219. Song JH, Huang CS, Nagata K, Yeh JZ, Narahashi T. Differential action of riluzole on tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels. J Pharmacol Exp Ther 1997; 282: 707-714.
220. + current and activation of BKCa channels in cultured differentiated human skeletal muscle cells. Life Sci 2008; 82: 11-20.
221. Bellingham MC. A review of the neural mechanisms of action and clinical efficiency of riluzole in treating amyotrophic lateral sclerosis: what have we learned in the last decade? CNS Neurosci Ther 2011; 17: 4-31.
222. Wang SJ, Wang KY, Wang WC. Mechanisms underlying the rilu-zole inhibition of glutamate release from rat cerebral cortex nerve terminals (synaptosomes). Neuroscience 2004; 125: 191-201.
223. Le MN, Chan JL, Rosenberg SA, Nabatian AS, Merrigan KT, Cohen-Solal KA, et al. The glutamate release inhibitor Riluzole decreases migration, invasion, and proliferation of melanoma cells. J Invest Dermatol 2010; 130: 2240-2249.
224. 2+ currents and modulates release of glutamate via presynaptic NMDA receptors on neonatal rat hypoglossal motoneurons in vitro. Eur J Neurosci 2008; 27: 2501-2514.
225. Speyer CL, Smith JS, Banda M, DeVries JA, Mekani T, Gorski DH, et al. Metabotropic glutamate receptor-1: A potential therapeutic target for the treatment of breast cancer. Breast Cancer Res Treat 2012; 132: 565-573.
226. Shi, M., Li, D., Xu, L. Method for preparation of ranolazine. WO2011160396 (2011).
227. Subarrao, A.V., Saidugari S. Novel solid state forms of ranolazine salts. US2011300218 (2011).
228. Artico, R., Adami, M., Barbareschi, D., Moscoso, J., Oldoni, T., Mascagni, P. Riluzole aqueous suspensions. US20120039953 (2012).
229. Bhasale, K., Nayak, R., Das, S., Thommandru, V.K. Sustained release composition of ranolazine. WO2011036677 (2011).
230. Yoshitake, M., Ga, K. Riluzole-containing transdermal patch. WO2010113225 (2010).
231. Belardinalli, L. Ranolazine for use for the treatment of pulmonary hypertension. WO2011159706 (2011).
232. Wang, W., Prokopczuk, E., Belardinelli, L., Lange, L., Jerling, M., Wolff, A. Use of ranolazine for the treatment of cardiovascular diseases. KR2011013352 (2011).
233. Antzelevitch, C., Belardinelli, L., Burashnikov, A., Shryock, J., Zeng, D. Method of treating atrial fibrillation. WO2011084733 (2011).
234. Belardinalli, L., Hoyer, K., Shryock, J. Co-administration of rano-lazine and cardiac glycosides. WO2010068461 (2010).
235. Diamond, I., Belardinelli, L., Shryock, J., Rajamani, S. Use of ranolazine for treating pain. WO2009100380 (2009).
236. Cheah BC, Vucic S, Krishnan AV, Kiernan MC. Riluzole, neuro-protection and amyotrophic lateral sclerosis. Curr Med Chem 2010; 17: 1942-1959.
237. Nishii, M., Funakoshi, Y., Imagawa, M., Abe, S., Kuwayama, T. Pharmaceutical for protection of motor nerve in patients with amyotrophic lateral sclerosis. KR20080066014 (2008).
238. Polman, C. Use of riluzole for the treatment of multiple sclerosis. US2008214631 (2008).
239. Rothstein JD. Excitotoxicity hypothesis. Neurology 1996; 47(Suppl 2):S19-S25.
240. Khanshmann, A., Al'Tkhaus, M., Gebauehr, A., Parsons, K.G.R., Danysh, V. New combinations of meramexane for treating neurodegenerative disorders. RU2432161C1 (2011).
241. Owen RT. Glutamatergic approaches in major depressive disorder: Focus on ketamine, memantine and riluzole. Drugs Today (Barc) 2012; 48: 469-478.
242. Goydos, J.S., Chen, S. Methods and compositions for treating cancer. US2010221246 (2010).
243. Lyons SA, Chung WJ, Weaver AK, Ogunrinu T, Sontheimer H. Autocrine glutamate signalling promotes glioma cell invasion. Cancer Res 2007; 67: 9463-9471.
244. Seidlitz EP, Sharma MK, Saikali Z, Ghert M, Singh G. Cancer cell lines release glutamate into the extracellular environment. Clin Exp Metastasis 2009; 26: 781-787.
245. Ye ZC, Sontheimer H. Glioma cells release excitotoxic concentrations of glutamate. Cancer Res 1999; 59: 4383-4391.
246. Busserolles, J., Alloui, A., Lazdunski, M., Eschalier, A. Use of riluzole to treat or prevent the adverse effects of antineoplastic agents. WO2011107710 (2011).
247. Djamgoz, M.B.A. Treatment of cancer/inhibition of metastasis. WO2012049440 (2012).
248. Riluzole in Women With Stage I, Stage II, or Stage IIIA Breast Cancer. Available at: http://clinicaltrials.gov/show/NCT00903214.
249. Riluzole in Treating Patients With Stage III or Stage IV Melanoma That Cannot Be Removed by Surgery. Available at: http://clinicaltrials.gov/show/NCT00866840.
250. Riluzole and Whole-Brain Radiation Therapy in Treating Patients With Brain Metastases. Available at: http://clinicaltrials.gov/show/NCT01018836.
251. Khan AJ, Wall B, Ahlawat S, Green C, Schiff D, Mehnert JM, et al. Riluzole enhances ionizing radiation-induced cytotoxicity in human melanoma cells that ectopically express metabotropic glu-tamate receptor 1 in vitro and in vivo. Clin Cancer Res 2011; 17: 1807-1814.
252. Suckow MA, Gutierrez LS, Risatti CA, Wolter WR, Taylor RE, Pollard M, et al. The anti-ischemia agent ranolazine promotes the development of intestinal tumours in APC(Min/+) mice. Cancer Lett 2004; 209:165-169.
253. Koren MJ, Crager MR, Sweeney M. Long-term safety of a novel antianginal agent in patients with severe chronic stable angina: The Ranolazine Open Label Experience (ROLE). J Am Coll Cardiol 2007; 49:1027-1034.
254. Pouyssegur J, Dayan F, Mazure NM. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 2006; 441: 437-443.
255. Canning MT, Postovit LM, Clarke SH, Graham CH. Oxygen-mediated regulation of gelatinase and tissue inhibitor of metallo-proteinases-1 expression by invasive cells. Exp Cell Res 2001; 267: 88-94.
256. Burke B, Giannoudis A, Corke KP, Gill D, Wells M, Ziegler-Heitbrock L, et al. Hypoxia-induced gene expression in human macrophages: implications for ischemic tissues and hypoxia-regulated gene therapy. Am J Pathol 2003; 163: 1233-1243.
257. Brat DJ, Castellano-Sanchez AA, Hunter SB, Pecot M, Cohen C, Hammond EH, et al. Pseudopalisades in glioblastoma are hypoxic, express extracellular matrix proteases, and are formed by an actively migrating cell population. Cancer Res 2004; 64: 920-927.
258. Ridgway PF, Ziprin P, Alkhamesi N, Paraskeva PA, Peck DH, Darzi AW. Hypoxia augments gelatinase activity in a variety of adenocarcinomas in vitro. J Surg Res 2005; 124: 180-186.
259. http://scim.ag/olddrugs (NIH unveils plan to rescue old drugs).
260. Bocquet A, Sablayrolles S, Vacher B, Le Grand B. F 15845, a new blocker of the persistent sodium current prevents consequences of hypoxia in rat femoral artery. Br J Pharmacol 2010; 161: 405-15.