Advertisement

Molecular Mechanisms Regulating Expression and Function of Cancer-Associated Carbonic Anhydrase IX

  • Jaromir Pastorek
  • Silvia Pastorekova
Chapter
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

Hypoxia and acidosis are typical physiological factors of tumor microenvironment acting in concert to support invasive and metastatic propensity of tumor cells through rearrangement of their gene expression profile and remodeling of their phenotype. Induction of carbonic anhydrase IX (CA IX) has recently been recognized as one of the important molecular events observed in tumor cells exposed to hypoxia. CA IX can serve as a “tag” of hypoxic areas in many tumor types and thereby provides a diagnostic tool as well as a target for selective delivery of anticancer immunotherapy. Moreover, CA IX actively contributes to pH regulation which protects tumor cells from acidosis and thereby provides a target for anticancer therapy based on reduction of tumor cell survival via inhibition of CA IX enzyme activity. Both aspects attract considerable attention but their full appraisal and further development require deeper understanding of the mechanisms behind CA IX expression and functioning. Here, we summarize and discuss the “state of the art” of CA IX field in context of its relevance for tumor microenvironment.

Keywords

Renal Cell Carcinoma Renal Cell Carcinoma Extracellular Acidosis Cell Renal Cell Carcinoma Clear Cell Renal Cell Carcinoma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Abbate F, Casini A, Owa T, Scozzafava A, Supuran CT (2004) Carbonic anhydrase inhibitors: E7070, a sulfonamide anticancer agent, potently inhibits cytosolic isozymes I and II, and transmembrane, tumor-associated isozyme IX. Bioorg Med Chem Lett 14:217–223PubMedGoogle Scholar
  2. Ahlskog JK, Dumelin CE, Trussel S, Marlind J, Neri D (2009a) In vivo targeting of tumor-associated carbonic anhydrases using acetazolamide derivatives. Bioorg Med Chem Lett 19:4851–4856PubMedGoogle Scholar
  3. Ahlskog JK, Schliemann C, Marlind J, Qureshi U, Ammar A, Pedley RB, Neri D (2009b) Human monoclonal antibodies targeting carbonic anhydrase IX for the molecular imaging of hypoxic regions in solid tumours. Br J Cancer 101:645–657PubMedGoogle Scholar
  4. Alterio V, Hilvo M, Di Fiore A, Supuran CT, Pan P, Parkkila S, Scaloni A, Pastorek J, Pastorekova S, Pedone C, Scozzafava A, Monti SM, De Simone G (2009) Crystal structure of the catalytic domain of the tumor-associated human carbonic anhydrase IX. Proc Natl Acad Sci USA 106:16233–16238PubMedGoogle Scholar
  5. Ashida S, Nishimori I, Tanimura M, Onishi S, Shuin T (2002) Effects of von Hippel-Lindau gene mutation and methylation status on expression of transmembrane carbonic anhydrases in renal cell carcinoma. J Cancer Res Clin Oncol 128:561–568PubMedGoogle Scholar
  6. Atkins M, Regan M, McDermott D, Mier J, Stanbridge E, Youmans A, Febbo P, Upton M, Lechpammer M, Signoretti S (2005) Carbonic anhydrase IX expression predicts outcome of interleukin 2 therapy for renal cancer. Clin Cancer Res 11:3714–3721PubMedGoogle Scholar
  7. Barathova M, Takacova M, Holotnakova T, Gibadulinova A, Ohradanova A, Zatovicova M, Hulikova A, Kopacek J, Parkkila S, Supuran CT, Pastorekova S, Pastorek J (2008) Alternative splicing variant of the hypoxia marker carbonic anhydrase IX expressed independently of hypoxia and tumour phenotype. Br J Cancer 98:129–136PubMedGoogle Scholar
  8. Bartosova M, Parkkila S, Pohlodek K, Karttunen TJ, Galbavy S, Mucha V, Harris AL, Pastorek J, Pastorekova S (2002) Expression of carbonic anhydrase IX in breast is associated with malignant tissues and is related to overexpression of c-erbB2. J Pathol 197:314–321PubMedGoogle Scholar
  9. Brahimi-Horn MC, Pouyssegur J (2007) Hypoxia in cancer cell metabolism and pH regulation. Essays Biochem 43:165–178PubMedGoogle Scholar
  10. Brennan DJ, Jirstrom K, Kronblad A, Millikan RC, Landberg G, Duffy MJ, Ryden L, Gallagher WM, O’Brien SL (2006) CA IX is an independent prognostic marker in premenopausal breast cancer patients with one to three positive lymph nodes and a putative marker of radiation resistance. Clin Cancer Res 12:6421–6431PubMedGoogle Scholar
  11. Brouwers AH, Buijs WC, Oosterwijk E, Boerman OC, Mala C, De Mulder PH, Corstens FH, Mulders PF, Oyen WJ (2003a) Targeting of metastatic renal cell carcinoma with the chimeric monoclonal antibody G250 labeled with (131)I or (111)In: an intrapatient comparison. Clin Cancer Res 9:3953S–3960SPubMedGoogle Scholar
  12. Brouwers H, Frielink C, Oosterwijk E, Oyen WJ, Corstens FH, Boerman OC (2003b) Interferons can upregulate the expression of the tumor associated antigen G250-MN/CA IX, a potential target for (radio)immunotherapy of renal cell carcinoma. Cancer Biother Radiopharm 18:539–547PubMedGoogle Scholar
  13. Bui MH, Seligson D, Han KR, Pantuck AJ, Dorey FJ, Huang Y, Horvath S, Leibovich BC, Chopra S, Liao SY, Stanbridge E, Lerman MI, Palotie A, Figlin RA, Belldegrun AS (2003) Carbonic anhydrase IX is an independent predictor of survival in advanced renal clear cell carcinoma: implications for prognosis and therapy. Clin Cancer Res 9:802–811PubMedGoogle Scholar
  14. Camenisch G, Stroka DM, Gassmann M, Wenger RH (2001) Attenuation of HIF-1 DNA-binding activity limits hypoxia-inducible endothelin-1 expression. Pflugers Arch 443:240–249PubMedGoogle Scholar
  15. Carney WP (2007) Circulating oncoproteins HER2/neu, EGFR and CAIX (MN) as novel cancer biomarkers. Expert Rev Mol Diagn 7:309–319PubMedGoogle Scholar
  16. Casey JR (2006) Why bicarbonate? Biochem Cell Biol 84:930–939PubMedGoogle Scholar
  17. Cecchi A, Hulikova A, Pastorek J, Pastorekova S, Scozzafava A, Winum JY, Montero JL, Supuran CT (2005) Carbonic anhydrase inhibitors. Design of fluorescent sulfonamides as probes of tumor-associated carbonic anhydrase IX that inhibit isozyme IX-mediated acidification of hypoxic tumors. J Med Chem 48:4834–4841PubMedGoogle Scholar
  18. Cecchi A, Winum JY, Innocenti A, Vullo D, Montero JL, Scozzafava A, Supuran CT (2004) Carbonic anhydrase inhibitors: synthesis and inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, and IX with sulfonamides derived from 4-isothiocyanato-benzolamide. Bioorg Med Chem Lett 14:5775–5780PubMedGoogle Scholar
  19. Coleman ML, Ratcliffe PJ (2007) Oxygen sensing and hypoxia-induced responses. Essays Biochem 43:1–15PubMedGoogle Scholar
  20. Crabb SJ, Bajdik CD, Leung S, Speers CH, Kennecke H, Huntsman DG, Gelmon KA (2008) Can clinically relevant prognostic subsets of breast cancer patients with four or more involved axillary lymph nodes be identified through immunohistochemical biomarkers? A tissue microarray feasibility study. Breast Cancer Res 10:R6PubMedGoogle Scholar
  21. D’Ambrosio K, Vitale RM, Dogne JM, Masereel B, Innocenti A, Scozzafava A, De Simone G, Supuran CT (2008) Carbonic anhydrase inhibitors: bioreductive nitro-containing sulfonamides with selectivity for targeting the tumor associated isoforms IX and XII. J Med Chem 51:3230–3237PubMedGoogle Scholar
  22. De Schutter H, Landuyt W, Verbeken E, Goethals L, Hermans R, Nuyts S (2005) The prognostic value of the hypoxia markers CA IX and GLUT 1 and the cytokines VEGF and IL 6 in head and neck squamous cell carcinoma treated by radiotherapy +/– chemotherapy. BMC Cancer 5:42Google Scholar
  23. Divgi CR, Pandit-Taskar N, Jungbluth AA, Reuter VE, Gonen M, Ruan S, Pierre C, Nagel A, Pryma DA, Humm J, Larson SM, Old LJ, Russo P (2007) Preoperative characterisation of clear-cell renal carcinoma using iodine-124-labelled antibody chimeric G250 (124I-cG250) and PET in patients with renal masses: a phase I trial. Lancet Oncol 8:304–310Google Scholar
  24. Dorai T, Sawczuk IS, Pastorek J, Wiernik PH, Dutcher JP (2005) The role of carbonic anhydrase IX overexpression in kidney cancer. Eur J Cancer 41:2935–2947Google Scholar
  25. Driessen A, Landuyt W, Pastorekova S, Moons J, Goethals L, Haustermans K, Nafteux P, Penninckx F, Geboes K, Lerut T, Ectors N (2006) Expression of carbonic anhydrase IX (CA IX), a hypoxia-related protein, rather than vascular-endothelial growth factor (VEGF), a pro-angiogenic factor, correlates with an extremely poor prognosis in esophageal and gastric adenocarcinomas. Ann Surg 243:334–340Google Scholar
  26. Dubois L, Douma K, Supuran CT, Chiu RK, van Zandvoort MA, Pastorekova S, Scozzafava A, Wouters BG, Lambin P (2007) Imaging the hypoxia surrogate marker CA IX requires expression and catalytic activity for binding fluorescent sulfonamide inhibitors. Radiother Oncol 83:367–373Google Scholar
  27. Dubois L, Lieuwes NG, Maresca A, Thiry A, Supuran CT, Scozzafava A, Wouters BG, Lambin P (2009) Imaging of CA IX with fluorescent labelled sulfonamides distinguishes hypoxic and (re)-oxygenated cells in a xenograft tumour model. Radiother Oncol 92:423–428Google Scholar
  28. Durrbach A, Angevin E, Poncet P, Rouleau M, Chavanel G, Chapel A, Thierry D, Gorter A, Hirsch R, Charpentier B, Senik A, Hirsch F (1999) Antibody-mediated endocytosis of G250 tumor-associated antigen allows targeted gene transfer to human renal cell carcinoma in vitro. Cancer Gene Ther 6:564–571Google Scholar
  29. Eckert AW, Lautner MH, Schutze A, Bolte K, Bache M, Kappler M, Schubert J, Taubert H, Bilkenroth U (2010) Co-expression of Hif1alpha and CAIX is associated with poor prognosis in oral squamous cell carcinoma patients. J Oral Pathol Med 39:313–317PubMedGoogle Scholar
  30. Fukumura D, Jain RK (2007) Tumor microenvironment abnormalities: causes, consequences, and strategies to normalize. J Cell Biochem 101:937–949Google Scholar
  31. Garaj V, Puccetti L, Fasolis G, Winum JY, Montero JL, Scozzafava A, Vullo D, Innocenti A, Supuran CT (2004) Carbonic anhydrase inhibitors: synthesis and inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, and IX with sulfonamides incorporating 1,2,4-triazine moieties. Bioorg Med Chem Lett 14:5427–5433Google Scholar
  32. Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4:891–899Google Scholar
  33. Generali D, Berruti A, Brizzi MP, Campo L, Bonardi S, Wigfield S, Bersiga A, Allevi G, Milani M, Aguggini S, Gandolfi V, Dogliotti L, Bottini A, Harris AL, Fox SB (2006a) Hypoxia-inducible factor-1alpha expression predicts a poor response to primary chemoendocrine therapy and disease-free survival in primary human breast cancer. Clin Cancer Res 12:4562–4568Google Scholar
  34. Generali D, Fox SB, Berruti A, Brizzi MP, Campo L, Bonardi S, Wigfield SM, Bruzzi P, Bersiga A, Allevi G, Milani M, Aguggini S, Dogliotti L, Bottini A, Harris AL (2006b) Role of carbonic anhydrase IX expression in prediction of the efficacy and outcome of primary epirubicin/tamoxifen therapy for breast cancer. Endocr Relat Cancer 13:921–930Google Scholar
  35. Gut MO, Parkkila S, Vernerova Z, Rohde E, Zavada J, Hocker M, Pastorek J, Karttunen T, Gibadulinova A, Zavadova Z, Knobeloch KP, Wiedenmann B, Svoboda J, Horak I, Pastorekova S (2002) Gastric hyperplasia in mice with targeted disruption of the carbonic anhydrase gene Car9. Gastroenterology 123:1889–1903PubMedGoogle Scholar
  36. Haapasalo J, Nordfors K, Jarvela S, Bragge H, Rantala I, Parkkila AK, Haapasalo H, Parkkila S (2007) Carbonic anhydrase II in the endothelium of glial tumors: a potential target for therapy. Neuro Oncol 9:308–313Google Scholar
  37. Haapasalo JA, Nordfors KM, Hilvo M, Rantala IJ, Soini Y, Parkkila AK, Pastorekova S, Pastorek J, Parkkila SM, Haapasalo HK (2006) Expression of carbonic anhydrase IX in astrocytic tumors predicts poor prognosis. Clin Cancer Res 12:473–477Google Scholar
  38. Harris AL (2002) Hypoxia – a key regulatory factor in tumour growth. Nat Rev Cancer 2:38–47Google Scholar
  39. Helmlinger G, Sckell A, Dellian M, Forbes NS, Jain RK (2002) Acid production in glycolysis-impaired tumors provides new insights into tumor metabolism. Clin Cancer Res 8:1284–1291PubMedGoogle Scholar
  40. Helmlinger G, Yuan F, Dellian M, Jain RK (1997) Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nat Med 3:177–182Google Scholar
  41. Hewett-Emmett D, Tashian RE (1996) Functional diversity, conservation, and convergence in the evolution of the alpha-, beta-, and gamma-carbonic anhydrase gene families. Mol Phylogenet Evol 5:50–77Google Scholar
  42. Hilvo M, Baranauskiene L, Salzano AM, Scaloni A, Matulis D, Innocenti A, Scozzafava A, Monti SM, Di Fiore A, De Simone G, Lindfors M, Janis J, Valjakka J, Pastorekova S, Pastorek J, Kulomaa MS, Nordlund HR, Supuran CT, Parkkila S (2008) Biochemical characterization of CA IX, one of the most active carbonic anhydrase isozymes. J Biol Chem 283:27799–27809Google Scholar
  43. Hirota K, Semenza GL (2005) Regulation of hypoxia-inducible factor 1 by prolyl and asparaginyl hydroxylases. Biochem Biophys Res Commun 338:610–616Google Scholar
  44. Holotnakova T, Tylkova L, Takacova M, Kopacek J, Petrik J, Pastorekova S, Pastorek, J (2010) Role of the HBx oncoprotein in carbonic anhydrase 9 induction. J Med Virol 82:32–40PubMedGoogle Scholar
  45. Hulikova A, Zatovicova M, Svastova E, Ditte P, Brasseur R, Kettmann R, Supuran CT, Kopacek J, Pastorek J, Pastorekova S (2009) Intact intracellular tail is critical for proper functioning of the tumor-associated, hypoxia-regulated carbonic anhydrase IX. FEBS Lett 583:3563–3568PubMedGoogle Scholar
  46. Hussain SA, Ganesan R, Reynolds G, Gross L, Stevens A, Pastorek J, Murray PG, Perunovic B, Anwar MS, Billingham L, James ND, Spooner D, Poole CJ, Rea DW, Palmer DH (2007) Hypoxia-regulated carbonic anhydrase IX expression is associated with poor survival in patients with invasive breast cancer. Br J Cancer 96:104–109Google Scholar
  47. Hussain SA, Palmer DH, Ganesan R, Hiller L, Gregory J, Murray PG, Pastorek J, Young L, James ND (2004) Carbonic anhydrase IX, a marker of hypoxia: correlation with clinical outcome in transitional cell carcinoma of the bladder. Oncol Rep 11:1005–1010PubMedGoogle Scholar
  48. Chia SK, Wykoff CC, Watson PH, Han C, Leek RD, Pastorek J, Gatter KC, Ratcliffe P, Harris AL (2001) Prognostic significance of a novel hypoxia-regulated marker, carbonic anhydrase IX, in invasive breast carcinoma. J Clin Oncol 19:3660–3668Google Scholar
  49. Chiang WL, Chu SC, Yang SS, Li MC, Lai JC, Yang SF, Chiou HL, Hsieh YS (2002) The aberrant expression of cytosolic carbonic anhydrase and its clinical significance in human non-small cell lung cancer. Cancer Lett 188:199–205Google Scholar
  50. Chiche J, Ilc K, Brahimi-Horn MC, Pouyssegur J (2010) Membrane-bound carbonic anhydrases are key pH regulators controlling tumor growth and cell migration. Adv Enzyme Regul 50:20–33Google Scholar
  51. Chiche J, Ilc K, Laferriere J, Trottier E, Dayan F, Mazure NM, Brahimi-Horn MC, Pouyssegur J (2009b) Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH. Cancer Res 69:358–368Google Scholar
  52. Cho M, Grabmaier K, Kitahori Y, Hiasa Y, Nakagawa Y, Uemura H, Hirao Y, Ohnishi T, Yoshikawa K, Ooesterwijk E (2000) Activation of the MN/CA9 gene is associated with hypomethylation in human renal cell carcinoma cell lines. Mol Carcinog 27:184–189Google Scholar
  53. Choi SW, Kim JY, Park JY, Cha IH, Kim J, Lee S (2008) Expression of carbonic anhydrase IX is associated with postoperative recurrence and poor prognosis in surgically treated oral squamous cell carcinoma. Hum Pathol 39:1317–1322PubMedGoogle Scholar
  54. Ihnatko R, Kubes M, Takacova M, Sedlakova O, Sedlak J, Pastorek J, Kopacek J, Pastorekova S (2006) Extracellular acidosis elevates carbonic anhydrase IX in human glioblastoma cells via transcriptional modulation that does not depend on hypoxia. Int J Oncol 29:1025–1033PubMedGoogle Scholar
  55. Ilies MA, Vullo D, Pastorek J, Scozzafava A, Ilies M, Caproiu MT, Pastorekova S, Supuran CT (2003) Carbonic anhydrase inhibitors. Inhibition of tumor-associated isozyme IX by halogenosulfanilamide and halogenophenylaminobenzolamide derivatives. J Med Chem 46:2187–2196Google Scholar
  56. Innocenti A, Pastorekova S, Pastorek J, Scozzafava A, De Simone G, Supuran CT (2009) The proteoglycan region of the tumor-associated carbonic anhydrase isoform IX acts as anintrinsic buffer optimizing CO2 hydration at acidic pH values characteristic of solid tumors. Bioorg Med Chem Lett 19:5825–5828Google Scholar
  57. Innocenti A, Vullo D, Scozzafava A, Casey JR, Supuran C (2005) Carbonic anhydrase inhibitors. Interaction of isozymes I, II, IV, V, and IX with carboxylates. Bioorg Med Chem Lett 15:573–578Google Scholar
  58. Ivanov S, Liao SY, Ivanova A, Danilkovitch-Miagkova A, Tarasova N, Weirich G, Merrill MJ, Proescholdt MA, Oldfield EH, Lee J, Zavada J, Waheed A, Sly W, Lerman MI, Stanbridge EJ (2001) Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer. Am J Pathol 158:905–919Google Scholar
  59. Ivanov SV, Kuzmin I, Wei MH, Pack S, Geil L, Johnson BE, Stanbridge EJ, Lerman MI (1998) Down-regulation of transmembrane carbonic anhydrases in renal cell carcinoma cell lines by wild-type von Hippel-Lindau transgenes. Proc Natl Acad Sci USA 95:12596–12601PubMedGoogle Scholar
  60. Jakubickova L, Biesova Z, Pastorekova S, Kettmann R, Pastorek J (2005) Methylation of the CA9 promoter can modulate expression of the tumor-associated carbonic anhydrase IX in dense carcinoma cell lines. Int J Oncol 26:1121–1127PubMedGoogle Scholar
  61. Jarvela S, Parkkila S, Bragge H, Kahkonen M, Parkkila AK, Soini Y, Pastorekova S, Pastorek J, Haapasalo H (2008) Carbonic anhydrase IX in oligodendroglial brain tumors. BMC Cancer 8:1Google Scholar
  62. Kaluz S, Kaluzova M, Chrastina A, Olive PL, Pastorekova S, Pastorek J, Lerman MI, Stanbridge EJ (2002) Lowered oxygen tension induces expression of the hypoxia marker MN/carbonic anhydrase IX in the absence of hypoxia-inducible factor 1 alpha stabilization: a role for phosphatidylinositol 3′-kinase. Cancer Res 62:4469–4477PubMedGoogle Scholar
  63. Kaluz S, Kaluzova M, Liao SY, Lerman M, Stanbridge EJ (2009) Transcriptional control of the tumor- and hypoxia-marker carbonic anhydrase 9: a one transcription factor (HIF-1) show? Biochim Biophys Acta 1795:162–172Google Scholar
  64. Kaluz S, Kaluzova M, Opavsky R, Pastorekova S, Gibadulinova A, Dequiedt F, Kettmann R, Pastorek J (1999) Transcriptional regulation of the MN/CA 9 gene coding for the tumor-associated carbonic anhydrase IX. Identification and characterization of a proximal silencer element. J Biol Chem 274:32588–32595PubMedGoogle Scholar
  65. Kappler M, Taubert H, Holzhausen HJ, Reddemann R, Rot S, Becker A, Kuhnt T, Dellas K, Dunst J, Vordermark D, Hansgen G, Bache M (2008) Immunohistochemical detection of HIF-1alpha and CAIX in advanced head-and-neck cancer. Prognostic role and correlation with tumor markers and tumor oxygenation parameters. Strahlenther Onkol 184:393–399Google Scholar
  66. Karumanchi SA, Jiang L, Knebelmann B, Stuart-Tilley AK, Alper SL, Sukhatme VP (2001) VHL tumor suppressor regulates Cl-/HCO3 - exchange and Na+/H+ exchange activities in renal carcinoma cells. Physiol Genomics 5:119–128Google Scholar
  67. Kim JY, Shin HJ, Kim TH, Cho KH, Shin KH, Kim BK, Roh JW, Lee S, Park SY, Hwang YJ, Han IO (2006) Tumor-associated carbonic anhydrases are linked to metastases in primary cervical cancer. J Cancer Res Clin Oncol 132:302–308Google Scholar
  68. Kim SJ, Rabbani ZN, Dewhirst MW, Vujaskovic Z, Vollmer RT, Schreiber EG, Oosterwijk E, Kelley MJ (2005) Expression of HIF-1alpha, CA IX, VEGF, and MMP-9 in surgically resected non-small cell lung cancer. Lung Cancer 49:325–335Google Scholar
  69. Kim SJ, Rabbani ZN, Vollmer RT, Schreiber EG, Oosterwijk E, Dewhirst MW, Vujaskovic Z, Kelley MJ (2004) Carbonic anhydrase IX in early-stage non-small cell lung cancer. Clin Cancer Res 10:7925–7933Google Scholar
  70. Kim SJ, Shin HJ, Jung KY, Baek SK, Shin BK, Choi J, Kim BS, Shin SW, Kim YH, Kim JS, Oosterwijk E (2007) Prognostic value of carbonic anhydrase IX and Ki-67 expression in squamous cell carcinoma of the tongue. Jpn J Clin Oncol 37:812–819Google Scholar
  71. Kirkpatrick JP, Rabbani ZN, Bentley RC, Hardee ME, Karol S, Meyer J, Oosterwijk E, Havrilesky L, Secord AA, Vujaskovic Z, Dewhirst MW, Jones EL (2008) Elevated CAIX expression is associated with an increased risk of distant failure in early-stage cervical cancer. Biomark Insights 3:45–55Google Scholar
  72. Kivela AJ, Saarnio J, Karttunen TJ, Kivela J, Parkkila AK, Pastorekova S, Pastorek J, Waheed A, Sly WS, Parkkila TS, Rajaniemi H (2001) Differential expression of cytoplasmic carbonic anhydrases, CA I and II, and membrane-associated isozymes, CA IX and XII, in normal mucosa of large intestine and in colorectal tumors. Dig Dis Sci 46:2179–2186Google Scholar
  73. Klatte T, Seligson DB, Rao JY, Yu H, de Martino M, Kawaoka K, Wong SG, Belldegrun AS, Pantuck AJ (2009) Carbonic anhydrase IX in bladder cancer: a diagnostic, prognostic, and therapeutic molecular marker. Cancer 115:1448–1458PubMedGoogle Scholar
  74. Kon-no H, Ishii G, Nagai K, Yoshida J, Nishimura M, Nara M, Fujii T, Murata Y, Miyamoto H, Ochiai A (2006) Carbonic anhydrase IX expression is associated with tumor progression and a poor prognosis of lung adenocarcinoma. Lung Cancer 54:409–418Google Scholar
  75. Kopacek J, Barathova M, Dequiedt F, Sepelakova J, Kettmann R, Pastorek J, Pastorekova S (2005) MAPK pathway contributes to density- and hypoxia-induced expression of the tumor-associated carbonic anhydrase IX. Biochim Biophys Acta 1729:41–49PubMedGoogle Scholar
  76. Korkeila E, Talvinen K, Jaakkola PM, Minn H, Syrjanen K, Sundstrom J, Pyrhonen S (2009) Expression of carbonic anhydrase IX suggests poor outcome in rectal cancer. Br J Cancer 100:874–880Google Scholar
  77. Korkolopoulou P, Perdiki M, Thymara I, Boviatsis E, Agrogiannis G, Kotsiakis X, Angelidakis D, Rologis D, Diamantopoulou K, Thomas-Tsagli E, Kaklamanis L, Gatter K, Patsouris E (2007) Expression of hypoxia-related tissue factors in astrocytic gliomas. A multivariate survival study with emphasis upon carbonic anhydrase IX. Hum Pathol 38:629–638Google Scholar
  78. Kowalewska M, Radziszewski J, Kulik J, Barathova M, Nasierowska-Guttmajer A, Bidzinski M, Pastorek J, Pastorekova S, Siedlecki JA (2005) Detection of carbonic anhydrase 9-expressing tumor cells in the lymph nodes of vulvar carcinoma patients by RT-PCR. Int J Cancer 116:957–962Google Scholar
  79. Kozin SV, Shkarin P, Gerweck LE (2001) The cell transmembrane pH gradient in tumors enhances cytotoxicity of specific weak acid chemotherapeutics. Cancer Res 61:4740–4743Google Scholar
  80. Kreis TE, Lodish HF (1986) Oligomerization is essential for transport of vesicular stomatitis viral glycoprotein to the cell surface. Cell 46:929–937Google Scholar
  81. Kummola L, Hamalainen JM, Kivela J, Kivela AJ, Saarnio J, Karttunen T, Parkkila S (2005) Expression of a novel carbonic anhydrase, CA XIII, in normal and neoplastic colorectal mucosa. BMC Cancer 5:41Google Scholar
  82. Kuo WH, Chiang WL, Yang SF, Yeh KT, Yeh CM, Hsieh YS, Chu SC (2003) The differential expression of cytosolic carbonic anhydrase in human hepatocellular carcinoma. Life Sci 73:2211–2223Google Scholar
  83. Lam JS, Pantuck AJ, Belldegrun AS, Figlin RA (2005) G250: a carbonic anhydrase IX monoclonal antibody. Curr Oncol Rep 7:109–115Google Scholar
  84. Lendahl U, Lee KL, Yang H, Poellinger L (2009) Generating specificity and diversity in the transcriptional response to hypoxia. Nat Rev Genet 10:821–832Google Scholar
  85. Li Y, Wang H, Oosterwijk E, Selman Y, Mira JC, Medrano T, Shiverick KT, Frost SC (2009) Antibody-specific detection of CAIX in breast and prostate cancers. Biochem Biophys Res Commun 386:488–492Google Scholar
  86. Liao SY, Aurelio ON, Jan K, Zavada J, Stanbridge EJ (1997) Identification of the MN/CA9 protein as a reliable diagnostic biomarker of clear cell carcinoma of the kidney. Cancer Res 57:2827–2831Google Scholar
  87. Liao SY, Brewer C, Zavada J, Pastorek J, Pastorekova S, Manetta A, Berman ML, DiSaia PJ, Stanbridge EJ (1994) Identification of the MN antigen as a diagnostic biomarker of cervical intraepithelial squamous and glandular neoplasia and cervical carcinomas. Am J Pathol 145:598–609Google Scholar
  88. Liao SY, Darcy KM, Randall LM, Tian C, Monk BJ, Burger RA, Fruehauf JP, Peters WA, Stock RJ, Stanbidge EJ (2010) Prognostic relevance of carbonic anhydrase-IX in high-risk, early-stage cervical cancer: A Gynecologic Oncology Group study. Gynecol Oncol 116:452–458Google Scholar
  89. Loncaster JA, Harris AL, Davidson SE, Logue JP, Hunter RD, Wycoff CC, Pastorek J, Ratcliffe PJ, Stratford IJ, West CM (2001) Carbonic anhydrase (CA IX) expression, a potential new intrinsic marker of hypoxia: correlations with tumor oxygen measurements and prognosis in locally advanced carcinoma of the cervix. Cancer Res 61:6394–6399Google Scholar
  90. Malentacchi F, Simi L, Nannelli C, Andreani M, Janni A, Pastorekova S, Orlando C (2009) Alternative splicing variants of carbonic anhydrase IX in human non-small cell lung cancer. Lung Cancer 64:271–276Google Scholar
  91. Mandriota SJ, Turner KJ, Davies DR, Murray PG, Morgan NV, Sowter HM, Wykoff CC, Maher ER, Harris AL, Ratcliffe PJ, Maxwell PH (2002) HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron. Cancer Cell 1:459–468Google Scholar
  92. Maresca A, Temperini C, Vu H, Pham NB, Poulsen SA, Scozzafava A, Quinn RJ, Supuran CT (2009) Non-zinc mediated inhibition of carbonic anhydrases: coumarins are a new class of suicide inhibitors (#). J Am Chem Soc 131:3057–3062Google Scholar
  93. Maseide K, Kandel RA, Bell RS, Catton CN, O’Sullivan B, Wunder JS, Pintilie M, Hedley D, Hill RP (2004) Carbonic anhydrase IX as a marker for poor prognosis in soft tissue sarcoma. Clin Cancer Res 10:4464–4471Google Scholar
  94. McKiernan JM, Buttyan R, Bander NH, Stifelman MD, Katz AE, Chen MW, Olsson CA, Sawczuk IS (1997) Expression of the tumor-associated gene MN: a potential biomarker for human renal cell carcinoma. Cancer Res 57:2362–2365Google Scholar
  95. McMurtrie HL, Cleary HJ, Alvarez BV, Loiselle FB, Sterling D, Morgan PE, Johnson DE, Casey JR (2004) The bicarbonate transport metabolon. J Enzyme Inhib Med Chem 19:231–236Google Scholar
  96. Morgan PE, Pastorekova S, Stuart-Tilley AK, Alper SL, Casey JR (2007) Interactions of transmembrane carbonic anhydrase, CAIX, with bicarbonate transporters. Am J Physiol Cell Physiol 293:C738–C748Google Scholar
  97. Mori M, Staniunas RJ, Barnard GF, Jessup JM, Steele GD Jr, Chen LB (1993) The significance of carbonic anhydrase expression in human colorectal cancer. Gastroenterology 105:820–826Google Scholar
  98. Morsy SM, Badawi AM, Cecchi A, Scozzafava A, Supuran CT (2009) Carbonic anhydrase inhibitors. Biphenylsulfonamides with inhibitory action towards the transmembrane, tumor-associated isozymes IX possess cytotoxic activity against human colon, lung and breast cancer cell lines. J Enzyme Inhib Med Chem 24:499–505Google Scholar
  99. Mulders P, Bleumer I, Debruyne F, Oosterwijk E (2004) Specific monoclonal antibody-based immunotherapy by targeting the RCC-associated antigen carbonic anhydrase-IX(G250/MN). Urologe A 43(Suppl 3):S146–S147PubMedGoogle Scholar
  100. Nakao M, Ishii G, Nagai K, Kawase A, Kenmotsu H, Kon-No H, Hishida T, Nishimura M, Yoshida J, Ochiai A (2009) Prognostic significance of carbonic anhydrase IX expression by cancer-associated fibroblasts in lung adenocarcinoma. Cancer 115:2732–2743Google Scholar
  101. Niemela AM, Hynninen P, Mecklin JP, Kuopio T, Kokko A, Aaltonen L, Parkkila AK, Pastorekova S, Pastorek J, Waheed A, Sly WS, Orntoft TF, Kruhoffer M, Haapasalo H, Parkkila S, Kivela AJ (2007) Carbonic anhydrase IX is highly expressed in hereditary nonpolyposis colorectal cancer. Cancer Epidemiol Biomarkers Prev 16:1760–1766PubMedGoogle Scholar
  102. Oosterwijk E (2008a) Carbonic anhydrase IX/G250/MN: a molecule too good to be true? BJU Int 101:527–528Google Scholar
  103. Oosterwijk E (2008b) Carbonic anhydrase IX: historical and future perspectives. BJU Int 101(Suppl 4):2–7PubMedGoogle Scholar
  104. Opavsky R, Pastorekova S, Zelnik V, Gibadulinova A, Stanbridge EJ, Zavada J, Kettmann R, Pastorek J (1996) Human MN/CA9 gene, a novel member of the carbonic anhydrase family: structure and exon to protein domain relationships. Genomics 33:480–487PubMedGoogle Scholar
  105. Pantuck AJ, Klatte T, Seligson D, Atkins M, Belldegrun A (2008) Carbonic anhydrase IX as a predictive biomarker for clear cell renal cell carcinoma. J Clin Oncol 26:3105–3107; author reply 3107–3109Google Scholar
  106. Parkkila S, Innocenti A, Kallio H, Hilvo M, Scozzafava A, Supuran CT (2009) The protein tyrosine kinase inhibitors imatinib and nilotinib strongly inhibit several mammalian alpha-carbonic anhydrase isoforms. Bioorg Med Chem Lett 19:4102–4106Google Scholar
  107. Parkkila S, Rajaniemi H, Parkkila AK, Kivela J, Waheed A, Pastorekova S, Pastorek J, Sly WS (2000) Carbonic anhydrase inhibitor suppresses invasion of renal cancer cells in vitro. Proc Natl Acad Sci USA 97:2220–2224Google Scholar
  108. Parkkila S, Lasota J, Fietcher JA, Ou WB, Kivelä AJ, Nuorva K, Parkkila AK, Ollikainen J, Sly WS, Waheed A, Pastorekova S, Pastorek J, Isola J, Miettinen M (2010). Carbonic anhydrase II. A novel biomarker for gastrointestinal stromal tumors. Mod Pathol 23:743–750Google Scholar
  109. Pastorek J, Pastorekova S, Callebaut I, Mornon JP, Zelnik V, Opavsky R, Zat’ovicova M, Liao S, Portetelle D, Stanbridge EJ et al (1994) Cloning and characterization of MN, a human tumor-associated protein with a domain homologous to carbonic anhydrase and a putative helix-loop-helix DNA binding segment. Oncogene 9:2877–2888PubMedGoogle Scholar
  110. Pastorekova S, Casini A, Scozzafava A, Vullo D, Pastorek J, Supuran CT (2004a) Carbonic anhydrase inhibitors: the first selective, membrane-impermeant inhibitors targeting the tumor-associated isozyme IX. Bioorg Med Chem Lett 14:869–873PubMedGoogle Scholar
  111. Pastorekova S, Parkkila S, Parkkila AK, Opavsky R, Zelnik V, Saarnio J, Pastorek J (1997) Carbonic anhydrase IX, MN/CA IX: analysis of stomach complementary DNA sequence and expression in human and rat alimentary tracts. Gastroenterology 112:398–408PubMedGoogle Scholar
  112. Pastorekova S, Parkkila S, Pastorek J, Supuran CT (2004b) Carbonic anhydrases: current state of the art, therapeutic applications and future prospects. J Enzyme Inhib Med Chem 19:199–229PubMedGoogle Scholar
  113. Pastorekova S, Parkkila S, Zavada J (2006) Tumor-associated carbonic anhydrases and their clinical significance. Adv Clin Chem 42:167–216PubMedGoogle Scholar
  114. Pastorekova S, Zatovicova M, Pastorek J (2008) Cancer-associated carbonic anhydrases and their inhibition. Curr Pharm Des 14:685–698PubMedGoogle Scholar
  115. Pastorekova S, Zavadova Z, Kostal M, Babusikova O, Zavada J (1992) A novel quasi-viral agent, MaTu, is a two-component system. Virology 187:620–626PubMedGoogle Scholar
  116. Peles E, Nativ M, Campbell PL, Sakurai T, Martinez R, Lev S, Clary DO, Schilling J, Barnea G, Plowman GD, Grumet M, Schlessinger J (1995) The carbonic anhydrase domain of receptor tyrosine phosphatase beta is a functional ligand for the axonal cell recognition molecule contactin. Cell 82:251–260Google Scholar
  117. Potter C, Harris AL (2004) Hypoxia inducible carbonic anhydrase IX, marker of tumour hypoxia, survival pathway and therapy target. Cell Cycle 3:164–167Google Scholar
  118. Pouyssegur J, Dayan F, Mazure NM (2006) Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441:437–443Google Scholar
  119. Rafajova M, Zatovicova M, Kettmann R, Pastorek J, Pastorekova S (2004) Induction by hypoxia combined with low glucose or low bicarbonate and high posttranslational stability upon reoxygenation contribute to carbonic anhydrase IX expression in cancer cells. Int J Oncol 24:995–1004PubMedGoogle Scholar
  120. Raghunand N, Gatenby RA, Gillies RJ (2003) Microenvironmental and cellular consequences of altered blood flow in tumours. Br J Radiol 76 Spec No 1:S11–S22PubMedGoogle Scholar
  121. Raval RR, Lau KW, Tran MG, Sowter HM, Mandriota SJ, Li JL, Pugh CW, Maxwell PH, Harris AL, Ratcliffe PJ (2005) Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. Mol Cell Biol 25:5675–5686Google Scholar
  122. Ruas JL, Poellinger L (2005) Hypoxia-dependent activation of HIF into a transcriptional regulator. Semin Cell Dev Biol 16:514–522Google Scholar
  123. Saarnio J, Parkkila S, Parkkila AK, Haukipuro K, Pastorekova S, Pastorek J, Kairaluoma MI, Karttunen TJ (1998) Immunohistochemical study of colorectal tumors for expression of a novel transmembrane carbonic anhydrase, MN/CA IX, with potential value as a marker of cell proliferation. Am J Pathol 153:279–285Google Scholar
  124. Saczewski F, Slawinski J, Kornicka A, Brzozowski Z, Pomarnacka E, Innocenti A, Scozzafava A, Supuran CT (2006) Carbonic anhydrase inhibitors. Inhibition of the cytosolic human isozymes I and II, and the transmembrane, tumor-associated isozymes IX and XII with substituted aromatic sulfonamides activatable in hypoxic tumors. Bioorg Med Chem Lett 16:4846–4851Google Scholar
  125. Sansone P, Storci G, Giovannini C, Pandolfi S, Pianetti S, Taffurelli M, Santini D, Ceccarelli C, Chieco P, Bonafe M (2007) p66Shc/Notch-3 interplay controls self-renewal and hypoxia survival in human stem/progenitor cells of the mammary gland expanded in vitro as mammospheres. Stem Cells 25:807–815Google Scholar
  126. Scott FL, Stec B, Pop C, Dobaczewska MK, Lee JJ, Monosov E, Robinson H, Salvesen GS, Schwarzenbacher R, Riedl SJ (2009) The Fas-FADD death domain complex structure unravels signalling by receptor clustering. Nature 457:1019–1022PubMedGoogle Scholar
  127. Shin KH, Diaz-Gonzalez JA, Russell J, Chen Q, Burgman P, Li XF, Ling CC (2007) Detecting changes in tumor hypoxia with carbonic anhydrase IX and pimonidazole. Cancer Biol Ther 6:70–75Google Scholar
  128. Schrijvers ML, van der Laan BF, de Bock GH, Pattje WJ, Mastik MF, Menkema L, Langendijk JA, Kluin PM, Schuuring E, van der Wal JE (2008) Overexpression of intrinsic hypoxia markers HIF1alpha and CA-IX predict for local recurrence in stage T1-T2 glottic laryngeal carcinoma treated with radiotherapy. Int J Radiat Oncol Biol Phys 72:161–169Google Scholar
  129. Signoretti S, Regan M, Atkins M (2008) Carbonic anhydrase IX as a predictive biomarker of response to kidney cancer therapy. BJU Int 101(Suppl 4):31–35PubMedGoogle Scholar
  130. Smaine FZ, Winum JY, Montero JL, Regainia Z, Vullo D, Scozzafava A, Supuran CT (2007) Carbonic anhydrase inhibitors: Selective inhibition of the extracellular, tumor-associated isoforms IX and XII over isozymes I and II with glycosyl-thioureido-sulfonamides. Bioorg Med Chem Lett 17:5096–5100Google Scholar
  131. Smyth LG, O’Hurley G, O’Grady A, Fitzpatrick JM, Kay E, Watson RW (2010) Carbonic anhydrase IX expression in prostate cancer. Prostate Cancer Prostatic Dis 13:178–181PubMedGoogle Scholar
  132. Stiti M, Cecchi A, Rami M, Abdaoui M, Barragan-Montero V, Scozzafava A, Guari Y, Winum JY, Supuran CT (2008) Carbonic anhydrase inhibitor coated gold nanoparticles selectively inhibit the tumor-associated isoform IX over the cytosolic isozymes I and II. J Am Chem Soc 130:16130–16131PubMedGoogle Scholar
  133. Stock C, Schwab A (2009) Protons make tumor cells move like clockwork. Pflugers Arch 458:981–992Google Scholar
  134. Stubbs M, McSheehy PM, Griffiths JR, Bashford CL (2000) Causes and consequences of tumour acidity and implications for treatment. Mol Med Today 6:15–19Google Scholar
  135. Supuran CT (2007) Carbonic anhydrases as drug targets – an overview. Curr Top Med Chem 7:825–833PubMedGoogle Scholar
  136. Supuran CT (2008) Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov 7:168–181Google Scholar
  137. Svastova E, Hulikova A, Rafajova M, Zat’ovicova M, Gibadulinova A, Casini A, Cecchi A, Scozzafava A, Supuran CT, Pastorek J, Pastorekova S (2004) Hypoxia activates the capacity of tumor-associated carbonic anhydrase IX to acidify extracellular pH. FEBS Lett 577:439–445PubMedGoogle Scholar
  138. Svastova E, Zilka N, Zat’ovicova M, Gibadulinova A, Ciampor F, Pastorek J, Pastorekova S (2003) Carbonic anhydrase IX reduces E-cadherin-mediated adhesion of MDCK cells via interaction with beta-catenin. Exp Cell Res 290:332–345PubMedGoogle Scholar
  139. Swietach P, Patiar S, Supuran CT, Harris AL, Vaughan-Jones RD (2009) The role of carbonic anhydrase 9 in regulating extracellular and intracellular ph in three-dimensional tumor cell growths. J Biol Chem 284:20299–20310Google Scholar
  140. Swietach P, Wigfield S, Supuran CT, Harris AL, Vaughan-Jones RD (2008) Cancer-associated, hypoxia-inducible carbonic anhydrase IX facilitates CO2 diffusion. BJU Int 101 (Suppl 4):22–4PubMedGoogle Scholar
  141. Swinson DE, Jones JL, Richardson D, Wykoff C, Turley H, Pastorek J, Taub N, Harris AL, O’Byrne KJ (2003) Carbonic anhydrase IX expression, a novel surrogate marker of tumor hypoxia, is associated with a poor prognosis in non-small-cell lung cancer. J Clin Oncol 21:473–482Google Scholar
  142. Takacova M, Holotnakova T, Vondracek J, Machala M, Pencikova K, Gradin K, Poellinger L, Pastorek J, Pastorekova S, Kopacek J (2009) Role of aryl hydrocarbon receptor in modulation of the expression of the hypoxia marker carbonic anhydrase IX. Biochem J 419:419–425PubMedGoogle Scholar
  143. Takacova M, Holotnakova T, Barathova M, Pastorekova S, Kopacek J, Pastorek J (2010). Src induces expression of carbonic anhydrase IX via hypoxia-inducible factor 1. Oncol Rep 23:869–874Google Scholar
  144. Tan EY, Yan M, Campo L, Han C, Takano E, Turley H, Candiloro I, Pezzella F, Gatter KC, Millar EK, O’Toole SA, McNeil CM, Crea P, Segara D, Sutherland RL, Harris AL, Fox SB (2009) The key hypoxia regulated gene CAIX is upregulated in basal-like breast tumours and is associated with resistance to chemotherapy. Br J Cancer 100:405–411Google Scholar
  145. Teicher BA (2009) Acute and chronic in vivo therapeutic resistance. Biochem Pharmacol 77:1665–1673PubMedGoogle Scholar
  146. Teicher BA, Liu SD, Liu JT, Holden SA, Herman TS (1993) A carbonic anhydrase inhibitor as a potential modulator of cancer therapies. Anticancer Res 13:1549–1556PubMedGoogle Scholar
  147. Temperini C, Innocenti A, Mastrolorenzo A, Scozzafava A, Supuran CT (2007) Carbonic anhydrase inhibitors. Interaction of the antiepileptic drug sulthiame with twelve mammalian isoforms: kinetic and X-ray crystallographic studies. Bioorg Med Chem Lett 17:4866–4872PubMedGoogle Scholar
  148. Trastour C, Benizri E, Ettore F, Ramaioli A, Chamorey E, Pouyssegur J, Berra E (2007) HIF-1alpha and CA IX staining in invasive breast carcinomas: prognosis and treatment outcome. Int J Cancer 120:1451–1458PubMedGoogle Scholar
  149. Turner JR, Odze RD, Crum CP, Resnick MB (1997) MN antigen expression in normal, preneoplastic, and neoplastic esophagus: a clinicopathological study of a new cancer-associated biomarker. Hum Pathol 28:740–744Google Scholar
  150. van den Beucken T, Koritzinsky M, Niessen H, Dubois L, Savelkouls K, Mujcic H, Jutten B, Kopacek J, Pastorekova S, van der Kogel AJ, Lambin P, Voncken W, Rouschop KM, Wouters BG (2009a) Hypoxia-induced expression of carbonic anhydrase 9 is dependent on the unfolded protein response. J Biol Chem 284:24204–24212Google Scholar
  151. van den Beucken T, Ramaekers CH, Rouschop K, Koritzinsky M, Wouters BG (2009b) Deficient carbonic anhydrase 9 expression in UPR-impaired cells is associated with reduced survival in an acidic microenvironment. Radiother Oncol 92:437–442Google Scholar
  152. Vermylen P, Roufosse C, Burny A, Verhest A, Bosschaerts T, Pastorekova S, Ninane V, Sculier JP (1999) Carbonic anhydrase IX antigen differentiates between preneoplastic malignant lesions in non-small cell lung carcinoma. Eur Respir J 14:806–811Google Scholar
  153. Vleugel MM, Greijer AE, Shvarts A, van der Groep P, van Berkel M, Aarbodem Y, van Tinteren H, Harris AL, van Diest PJ, van der Wall E (2005) Differential prognostic impact of hypoxia induced and diffuse HIF-1alpha expression in invasive breast cancer. J Clin Pathol 58:172–177Google Scholar
  154. Vukovic V, Tannock IF (1997) Influence of low pH on cytotoxicity of paclitaxel, mitoxantrone and topotecan. Br J Cancer 75:1167–1172PubMedGoogle Scholar
  155. Vullo D, Franchi M, Gallori E, Pastorek J, Scozzafava A, Pastorekova S, Supuran CT (2003) Carbonic anhydrase inhibitors: inhibition of the tumor-associated isozyme IX with aromatic and heterocyclic sulfonamides. Bioorg Med Chem Lett 13:1005–1009PubMedGoogle Scholar
  156. Vullo D, Scozzafava A, Pastorekova S, Pastorek J, Supuran CT (2004) Carbonic anhydrase inhibitors: inhibition of the tumor-associated isozyme IX with fluorine-containing sulfonamides. The first subnanomolar CA IX inhibitor discovered. Bioorg Med Chem Lett 14:2351–2356Google Scholar
  157. Weber A, Casini A, Heine A, Kuhn D, Supuran CT, Scozzafava A, Klebe G (2004) Unexpected nanomolar inhibition of carbonic anhydrase by COX-2-selective celecoxib: new pharmacological opportunities due to related binding site recognition. J Med Chem 47:550–557Google Scholar
  158. Wilkinson BL, Bornaghi LF, Houston TA, Innocenti A, Supuran CT, Poulsen SA (2006) A novel class of carbonic anhydrase inhibitors: glycoconjugate benzene sulfonamides prepared by “click-tailing”. J Med Chem 49:6539–6548Google Scholar
  159. Willam C, Warnecke C, Schefold JC, Kugler J, Koehne P, Frei U, Wiesener M, Eckardt KU (2006) Inconsistent effects of acidosis on HIF-alpha protein and its target genes. Pflugers Arch 451:534–543Google Scholar
  160. Winum JY, Cecchi A, Montero JL, Innocenti A, Scozzafava A, Supuran CT (2005a) Carbonic anhydrase inhibitors. Synthesis and inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, and IX with boron-containing sulfonamides, sulfamides, and sulfamates: toward agents for boron neutron capture therapy of hypoxic tumors. Bioorg Med Chem Lett 15:3302–3306Google Scholar
  161. Winum JY, Dogne JM, Casini A, de Leval X, Montero JL, Scozzafava A, Vullo D, Innocenti A, Supuran CT (2005b) Carbonic anhydrase inhibitors: synthesis and inhibition of cytosolic/membrane-associated carbonic anhydrase isozymes I, II, and IX with sulfonamides incorporating hydrazino moieties. J Med Chem 48:2121–2125Google Scholar
  162. Winum JY, Pastorekova S, Jakubickova L, Montero JL, Scozzafava A, Pastorek J, Vullo D, Innocenti A, Supuran CT (2005c) Carbonic anhydrase inhibitors: synthesis and inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, and IX with bis-sulfamates. Bioorg Med Chem Lett 15:579–584Google Scholar
  163. Winum JY, Vullo D, Casini A, Montero JL, Scozzafava A, Supuran CT (2003a) Carbonic anhydrase inhibitors. Inhibition of cytosolic isozymes I and II and transmembrane, tumor-associated isozyme IX with sulfamates including EMATE also acting as steroid sulfatase inhibitors. J Med Chem 46:2197–2204Google Scholar
  164. Winum JY, Vullo D, Casini A, Montero JL, Scozzafava A, Supuran CT (2003b) Carbonic anhydrase inhibitors: inhibition of transmembrane, tumor-associated isozyme IX, and cytosolic isozymes I and II with aliphatic sulfamates. J Med Chem 46:5471–5477Google Scholar
  165. Wykoff CC, Beasley NJ, Watson PH, Turner KJ, Pastorek J, Sibtain A, Wilson GD, Turley H, Talks KL, Maxwell PH, Pugh CW, Ratcliffe PJ, Harris AL (2000) Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res 60:7075–7083Google Scholar
  166. Yin Q, Lin SC, Lamothe B, Lu M, Lo YC, Hura G, Zheng L, Rich RL, Campos AD, Myszka DG, Lenardo MJ, Darnay BG, Wu H (2009) E2 interaction and dimerization in the crystal structure of TRAF6. Nat Struct Mol Biol 16:658–666Google Scholar
  167. Yoshiura K, Nakaoka T, Nishishita T, Sato K, Yamamoto A, Shimada S, Saida T, Kawakami Y, Takahashi TA, Fukuda H, Imajoh-Ohmi S, Oyaizu N, Yamashita N (2005) Carbonic anhydrase II is a tumor vessel endothelium-associated antigen targeted by dendritic cell therapy. Clin Cancer Res 11:8201–8207Google Scholar
  168. Zat’ovicova M, Tarabkova K, Svastova E, Gibadulinova A, Mucha V, Jakubickova L, Biesova Z, Rafajova M, Ortova Gut M, Parkkila S, Parkkila AK, Waheed A, Sly WS, Horak I, Pastorek J, Pastorekova S (2003) Monoclonal antibodies generated in carbonic anhydrase IX-deficient mice recognize different domains of tumour-associated hypoxia-induced carbonic anhydrase IX. J Immunol Methods 282:117–134PubMedGoogle Scholar
  169. Zatovicova M, Sedlakova O, Svastova E, Ohradanova A, Ciampor F, Arribas J, Pastorek J, Pastorekova S (2005) Ectodomain shedding of the hypoxia-induced carbonic anhydrase IX is a metalloprotease-dependent process regulated by TACE/ADAM17. Br J Cancer 93:1267–1276PubMedGoogle Scholar
  170. Zatovicova M, Jeleuska L, Hulikova A, Csaderova L, Ditte P, Goliasova T, Pastorek J, Pastorekova S (in press). Carbonic anhydrase IX as an anticancer target: preclinical evaluation of internalizing monoclonal antibody directed to catalytic domain. Curr Pharm DesignPubMedGoogle Scholar
  171. Zavada J, Zavadova Z, Pastorek J, Biesova Z, Jezek J, Velek J (2000) Human tumour-associated cell adhesion protein MN/CA IX: identification of M75 epitope and of the region mediating cell adhesion. Br J Cancer 82:1808–1813PubMedGoogle Scholar
  172. Zavada J, Zavadova Z, Pastorekova S, Ciampor F, Pastorek J, Zelnik V (1993) Expression of MaTu-MN protein in human tumor cultures and in clinical specimens. Int J Cancer 54:268–274PubMedGoogle Scholar
  173. Zavada J, Zavadova Z, Zat’ovicova M, Hyrsl L, Kawaciuk I (2003) Soluble form of carbonic anhydrase IX (CA IX) in the serum and urine of renal carcinoma patients. Br J Cancer 89:1067–1071PubMedGoogle Scholar
  174. Zhang J (2008) Recent advances in preoperative imaging of renal tumors. Curr Opin Urol 18:111–115Google Scholar
  175. Zheng J, Avvaru BS, Tu C, McKenna R, Silverman DN (2008) Role of hydrophilic residues in proton transfer during catalysis by human carbonic anhydrase II. Biochemistry 47:12028–12036PubMedGoogle Scholar
  176. Zhou GX, Ireland J, Rayman P, Finke J, Zhou M (2010) Quantification of carbonic anhydrase IX expression in serum and tissue of renal cell carcinoma patients using enzyme-linked immunosorbent assay: prognostic and diagnostic potentials. Urology 75:257–261PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Molecular Medicine, Institute of VirologySlovak Academy of SciencesBratislavaSlovak Republic

Personalised recommendations