Teaching new dogs old tricks: Membrane biophysical properties in drug delivery and resistance

Recent Patents on Anti-Cancer Drug Discovery

Volumn 6, Issue 3, 2011, Pages 334-346

  Milosavljevic, Nina ^d   Blanchard, Adam ^a   Wahl, Miriam L ^c   Harguindey, Salvador ^b   Poet, Mallorie ^d   Counillon, Laurent ^d   Rauch, Cyril ^a  

^a UNIVERSITY OF NOTTINGHAM   (United Kingdom)

^b Institute of Clinical Biology and Metabolism   (Spain)

^c Department of Chemistry ^*  (United States)

^d UNIVERSITÉ CÔTE D'AZUR   (France)

Author keywords

Cell membrane; Drug delivery; Drug resistance; Pharmacokinetics; Physical biology

Indexed keywords

ADENOSINE TRIPHOSPHATASE (POTASSIUM SODIUM); ANGIOSTATIN; ANTINEOPLASTIC AGENT; BAFILOMYCIN A1; CARIPORIDE; CONCANAMYCIN A; DOXORUBICIN; GLYCOPROTEIN P; LIPID; LIPOSOME; MEMBRANE PROTEIN; MONENSIN; MONOCARBOXYLATE TRANSPORTER; NIGERICIN; PROTON TRANSPORTING ADENOSINE TRIPHOSPHATASE; PROTON TRANSPORTING ADENOSINE TRIPHOSPHATE SYNTHASE; RESVERATROL; SODIUM PROTON EXCHANGE PROTEIN; TAMOXIFEN; VERAPAMIL;

ACIDITY; ALKALINITY; ARTICLE; BIOPHYSICS; BREAST CANCER; CANCER CELL CULTURE; CELL MEMBRANE PERMEABILITY; CELL MEMBRANE POTENTIAL; CHEMOSENSITIZATION; DRUG DELIVERY SYSTEM; DRUG DIFFUSION; DRUG DISTRIBUTION; DRUG PENETRATION; DRUG RESISTANCE; DRUG RETENTION; DRUG TARGETING; ENDOCYTOSIS; ENZYME ACTIVITY; EXOCYTOSIS; GENE OVEREXPRESSION; HUMAN; INTRACELLULAR SPACE; LIPID BILAYER; LUNG CANCER; MATHEMATICAL ANALYSIS; MEMBRANE BIOLOGY; MULTIDRUG RESISTANCE; PATENT; PH; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN INTERACTION; UPREGULATION;

ANIMALS; ANTINEOPLASTIC AGENTS; BIOPHYSICS; CELL MEMBRANE; DOGS; DRUG DELIVERY SYSTEMS; DRUG RESISTANCE, MULTIPLE; DRUG RESISTANCE, NEOPLASM; HUMANS; MODELS, BIOLOGICAL; NEOPLASMS; SURFACE PROPERTIES; WIT AND HUMOR AS TOPIC;

EID: 80052317139     PISSN: 15748928     EISSN: None     Source Type: Journal    
DOI: 10.2174/157489211796957829     Document Type: Article

References (114)

1. Gajate C, Mollinedo F. Biological activities, mechanisms of action and biomedical prospect of the antitumor ether phospholipid ET- 18-OCH(3) (edelfosine), a proapoptotic agent in tumor cells. Curr Drug Metab 2002; 3(5): 491-525.
2. Torigoe T, Izumi H, Ise T, Murakami T, Uramoto H, Ishiguchi H, et al. Vacuolar H(+)-ATPase: functional mechanisms and potential as a target for cancer chemotherapy. Anticancer Drugs 2002; 13(3): 237-243.
3. Harguindey S, Reshkin SJ, Orive G, Arranz JL, Anitua E. Growth and trophic factors, pH and the Na+/H+ exchanger in Alzheimer's disease, other neurodegenerative diseases and cancer: new therapeutic possibilities and potential dangers. Curr Alzheimer Res 2007; 4(1): 53-65.
4. Devaux PF. Is lipid translocation involved during endo- and exocytosis? Biochimie 2000; 82(5): 497-509.
5. Pomorski T, Menon AK. Lipid flippases and their biological functions. Cell Mol Life Sci 2006; 63(24): 2908-2921.
6. Seigneuret M, Devaux PF. ATP-dependent asymmetric distribution of spin-labeled phospholipids in the erythrocyte membrane: relation to shape changes. Proc Natl Acad Sci USA 1984; 81(12): 3751-3755.
7. Devaux PF, Zachowski A, Morrot G, Cribier S, Fellmann P, Geldwerth D, et al. Control of the transmembrane phospholipids distribution in eukaryotic cells by aminophospholipid translocase. Biotechnol Appl Biochem 1990; 12(5): 517-522.
8. Farge E, Devaux PF. Shape changes of giant liposomes induced by an asymmetric transmembrane distribution of phospholipids. Biophys J 1992; 61(2): 347-357.
9. Miao L, Seifert U, Wortis M, Dobereiner HG. Budding transitions of fluid-bilayer vesicles: The effect of area-difference elasticity. Phys Rev E Stat Phys Plasmas Fluids Relat Interdiscip Topics 1994; 49(6): 5389-5407.
10. Cribier S, Sainte-Marie J, Devaux PF. Quantitative comparison between aminophospholipid translocase activity in human erythrocytes and in K562 cells. Biochim Biophys Acta 1993;1148(1): 85-90.
11. Farge E, Ojcius DM, Subtil A, Dautry-Varsat A. Enhancement of endocytosis due to aminophospholipid transport across the plasma membrane of living cells. Am J Physiol 1999; 276(3 Pt 1): C725-C733.
12. Rauch C, Farge E. Endocytosis switch controlled by transmembrane osmotic pressure and phospholipid number asymmetry. Biophys J 2000; 78(6): 3036-3047.
13. Nossal R, Zimmerberg J. Endocytosis: curvature to the ENTH degree. Curr Biol 2002; 12(22): R770-R772.
14. Itoh T, De Camilli P. BAR, F-BAR (EFC) and ENTH/ANTH domains in the regulation of membrane-cytosol interfaces and membrane curvature. Biochimica et biophysica acta 2006; 1761(8): 897-912.
15. Rauch C, Pluen A. Multi drug resistance-dependent vacuum cleaner functionality potentially driven by the interactions between endocytosis, drug size and Pgp-like transporters surface density. Eur Biophys J 2007; 36(2): 121-131.
16. Rauch C. Toward a mechanical control of drug delivery. On the relationship between Lipinski's 2nd rule and cytosolic pH changes in doxorubicin resistance levels in cancer cells: A comparison to published data. Eur Biophys J 2009; 38(7): 829-846.
17. Rauch C. On the relationship between drug's size, cell membrane mechanical properties and high levels of multi drug resistance: A comparison to published data. Eur Biophys J 2009; 38(4): 537-546.
18. Regev R, Yeheskely-Hayon D, Katzir H, Eytan GD. Transport of anthracyclines and mitoxantrone across membranes by a flip-flop mechanism. Biochem Pharmacol 2005; 70(1): 161-169.
19. Cirilli M, Bachechi F, Ughetto G, Colonna FP, Capobianco ML. Interactions between morpholinyl anthracyclines and DNA. The crystal structure of a morpholino doxorubicin bound to d(CGTACG). J Mol Biol 1993; 230(3): 878-889.
20. Heijn M, Roberge S, Jain RK. Cellular membrane permeability of anthracyclines does not correlate with their delivery in a tissueisolated tumor. Cancer Res 1999; 59(17): 4458-4463.
21. Bloom M, Evans E, Mouritsen OG. Physical properties of the fluid lipid-bilayer component of cell membranes: A perspective. Q Rev Biophys 1991; 24(3): 293-397.
22. Devaux PF, Zachowski A, Favre E, Fellmann P, Cribier S, Geldwerth D, et al. Energy-dependent translocation of aminophospholipids in the erythrocyte membrane. Biochimie 1986; 68(3): 383-393.
23. Farge E. Increased vesicle endocytosis due to an increase in the plasma membrane phosphatidylserine concentration. Biophys J 1995; 69(6): 2501-2506.
24. Altan N, Chen Y, Schindler M, Simon SM. Tamoxifen inhibits acidification in cells independent of the estrogen receptor. Proc Natl Acad Sci USA 1999; 96(8): 4432-4437.
25. Sehested M, Skovsgaard T, van Deurs B, Winther-Nielsen H. Increased plasma membrane traffic in daunorubicin resistant P388 leukaemic cells. Effect of daunorubicin and verapamil. Br J Cancer 1987; 56(6): 747-751.
26. Rauch C, Pluen A, Foster N, Loughna P, Mobasheri A, Lagadic- Gossmann D, et al. On some aspects of the thermodynamic of membrane recycling mediated by fluid phase endocytosis: Evaluation of published data and perspectives. Cell Biochem Biophys 2010; 56(2-3): 73-90.
27. Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I, Gottesman MM. Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol 1999; 39: 361-398.
28. Bornmann WG, Roepe PD. Analysis of drug transport kinetics in multidrug-resistant cells using a novel coumarin-vinblastine compound. Biochemistry 1994; 33(42): 12665-12675.
29. Eytan GD. Mechanism of multidrug resistance in relation to passive membrane permeation. Biomed Pharmacother 2005; 59(3): 90-97.
30. Germann UA. P-glycoprotein--a mediator of multidrug resistance in tumour cells. Eur J Cancer 1996; 32A(6): 927-944.
31. Nielsen D, Maare C, Skovsgaard T. Influx of daunorubicin in multidrug resistant Ehrlich ascites tumour cells: Correlation to expression of P-glycoprotein and efflux. Influence of verapamil. Biochem Pharmacol 1995; 50(4): 443-450.
32. Ramu A, Pollard HB, Rosario LM. Doxorubicin resistance in P388 leukemia--evidence for reduced drug influx. Int J Cancer 1989; 44(3): 539-547.
33. Raviv Y, Pollard HB, Bruggemann EP, Pastan I, Gottesman MM. Photosensitized labeling of a functional multidrug transporter in living drug-resistant tumor cells. J Biol Chem 1990; 265(7): 3975-3980.
34. Sharom FJ. The P-glycoprotein efflux pump: How does it transport drugs? J Membr Biol 1997; 160(3): 161-175.
35. Sirotnak FM, Yang CH, Mines LS, Oribe E, Biedler JL. Markedly altered membrane transport and intracellular binding of vincristine in multidrug-resistant Chinese hamster cells selected for resistance to vinca alkaloids. J Cell Physiol 1986; 126(2): 266-274.
36. Spoelstra EC, Westerhoff HV, Dekker H, Lankelma J. Kinetics of daunorubicin transport by P-glycoprotein of intact cancer cells. Eur J Biochem 1992; 207(2): 567-579.
37. Stein WD, Cardarelli C, Pastan I, Gottesman MM. Kinetic evidence suggesting that the multidrug transporter differentially handles influx and efflux of its substrates. Mol Pharmacol 1994; 45(4): 763-772.
38. Rudnick J, Gaspari G. Elements of the Random Walk. Cambridge: Cambridge University Press; 2004.
39. Ferte J. Analysis of the tangled relationships between Pglycoprotein- mediated multidrug resistance and the lipid phase of the cell membrane. Eur J Biochem / FEBS 2000; 267(2): 277-294.
40. Colin M, Madoulet C, Warren L, Jardillier JC. Alterations of vinblastine influx in multidrug-resistant lymphoblastic leukaemic CEM cells. Anticancer Res 1996; 16(1): 407-412.
41. Biedler JL, Riehm H. Cellular resistance to actinomycin-D in chinese hamster cells in vitro - cross-resistance, radioautographic, and cytogenetic studies. Cancer Res 1970; 30(4): 1174-1184.
42. Selassie CD, Hansch C, Khwaja TA. Structure Activity Relationships of Multidrug Resistance. In: Curtius H-C, Ghisla S, Blau N, editors. Chemistry and Biology of Pteridines, 1989: Pteridines and Folic Acid Derivatives. 9 th International Symposium on Pteridines and Folic Acid Derivatives Chemical, Biological, and Clinical Aspects; 1989 Sep 3-8; Zurich, Switzerland. Berlin: Walter de Gruyter and Co.; 1990, pp. 1217-1220.
43. Selassie CD, Hansch C, Khwaja TA. Structure-activityrelationships of antineoplastic agents in multidrug resistance. J Med Chem 1990; 33(7): 1914-1919.
44. Seelig A. The role of size and charge for blood-brain barrier permeation of drugs and fatty acids. J Mol Neurosci 2007; 33(1): 32-41.
45. Harguindey S, Orive G, Luis Pedraz J, Paradiso A, Reshkin SJ. The role of pH dynamics and the Na+/H+ antiporter in the etiopathogenesis and treatment of cancer. Two faces of the same coin--one single nature. Biochim Biophys Acta 2005; 1756(1): 1-24.
46. Harguindey S, Pedraz JL, Garcia Canero R, Perez de Diego J, Cragoe EJ, Jr. Hydrogen ion-dependent oncogenesis and parallel new avenues to cancer prevention and treatment using a H(+)- mediated unifying approach: pH-related and pH-unrelated mechanisms. Crit Rev Oncog 1995; 6(1): 1-33.
47. Perona R, Serrano R. Increased pH and tumorigenicity of fibroblasts expressing a yeast proton pump. Nature 1988; 334(6181): 438-440.
48. Reshkin SJ, Bellizzi A, Caldeira S, Albarani V, Malanchi I, Poignee M, et al. Na+/H+ exchanger-dependent intracellular alkalinization is an early event in malignant transformation and plays an essential role in the development of subsequent transformation-associated phenotypes. FASEB J 2000; 14(14): 2185-9217.
49. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100(1): 57-70.
50. Webb SD, Sherratt JA, Fish RG. Mathematical modelling of tumour acidity: regulation of intracellular pH. J Theor Biol 1999; 196(2): 237-250.
51. Roepe PD. PH and multidrug resistance. Novartis Found Symp 2001; 240: 232-247; discussion 47-50.
52. Raghunand N, Gillies RJ. PH and chemotherapy. Novartis Found Symp 2001; 240: 199-211; discussion 65-8.
53. Chen Q, Benson RS, Whetton AD, Brant SR, Donowitz M, Montrose MH, et al. Role of acid/base homeostasis in the suppression of apoptosis in haemopoietic cells by v-Abl protein tyrosine kinase. J Cell Sci 1997; 110 (Pt 3): 379-387.
54. Goossens JF, Henichart JP, Dassonneville L, Facompre M, Bailly C. Relation between intracellular acidification and camptothecininduced apoptosis in leukemia cells. Eur J Pharm Sci 2000; 10(2): 125-131.
55. Roepe PD, Wei LY, Cruz J, Carlson D. Lower electrical membrane potential and altered pHi homeostasis in multidrug-resistant (MDR) cells: Further characterization of a series of MDR cell lines expressing different levels of P-glycoprotein. Biochemistry 1993; 32(41): 11042-11056.
56. Simon S. The multiple mechanisms of multidrug resistance and cellular pH. Novartis Found Symp 2001; 240: 269-281; discussion 82-9.
57. Fidler IJ, Ellis LM. The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell 1994; 79(2): 185-188.
58. El Awad B, Kreft B, Wolber EM, Hellwig-Burgel T, Metzen E, Fandrey J, et al. Hypoxia and interleukin-1beta stimulate vascular endothelial growth factor production in human proximal tubular cells. Kidney Int 2000; 58(1): 43-50.
59. D'Arcangelo D, Facchiano F, Barlucchi LM, Melillo G, Illi B, Testolin L, et al. Acidosis inhibits endothelial cell apoptosis and function and induces basic fibroblast growth factor and vascularendothelial growth factor expression. Circ Res 2000; 86(3): 312-318.
60. Laurencot CM, Andrews PA, Kennedy KA. Inhibitors of intracellular pH regulation induce cisplatin resistance in EMT6 mouse mammary tumor cells. Oncol Res 1995; 7(7-8): 363-369.
61. Chau Q, Stewart DJ. Cisplatin efflux, binding and intracellular pH in the HTB56 human lung adenocarcinoma cell line and the E-8/0.7 cisplatin-resistant variant. Cancer Chemother harmacol 1999; 44(3): 193-202.
62. Barry MA, Reynolds JE, Eastman A. Etoposide-induced apoptosis in human HL-60 cells is associated with intracellular acidification. Cancer Res 1993; 53(10 Suppl): 2349-2357.
63. De Milito A, Fais S. Tumor acidity, chemoresistance and proton pump inhibitors. Future Oncol 2005; 1(6): 779-786.
64. Di Sario A, Bendia E, Omenetti A, De Minicis S, Marzioni M, Kleemann HW, et al. Selective inhibition of ion transport mechanisms regulating intracellular pH reduces proliferation and induces apoptosis in cholangiocarcinoma cells. Dig Liver Dis 2007; 39(1): 60-69.
65. Murakami T, Shibuya I, Ise T, Chen ZS, Akiyama S, Nakagawa M, et al. Elevated expression of vacuolar proton pump genes and cellular PH in cisplatin resistance. Int J Cancer 2001; 93(6): 869-874.
66. Keizer HG, Joenje H. Increased cytosolic pH in multidrug-resistant human lung tumor cells: Effect of verapamil. J Nat Cancer Inst 1989; 81(9): 706-709.
67. Roepe PD. The role of the MDR protein in altered drug translocation across tumor cell membranes. Biochim Biophys Acta 1995; 1241(3): 385-405.
68. Radvakova I, Mirossay A, Mojzis J, Mirossay L. The effect of 5'- (N,N-dimethyl)-amiloride on cytotoxic activity of doxorubicin and vincristine in CEM cell lines. Physiol Res 2001; 50(3): 283-7.
69. Goda K, Balkay L, Marian T, Tron L, Aszalos A, Szabo G, Jr. Intracellular pH does not affect drug extrusion by P-glycoprotein. J Photochem Photobiol B 1996; 34(2-3): 177-182.
70. Altenberg GA, Young G, Horton JK, Glass D, Belli JA, Reuss L. Changes in intra- or extracellular pH do not mediate Pglycoprotein-dependent multidrug resistance. Proc Natl Acad Sci USA 1993; 90(20): 9735-978.
71. Alberts B, Bray D, Lewis J, Raff M, Roberts K, Watson JD. Biologie Moleculaire de La Cellule. Inc. GP, Editor. New York 1994.
72. Petelska AD, Figaszewski ZA. Effect of pH on the interfacial tension of bilayer lipid membrane formed from phosphatidylcholine or phosphatidylserine. Biochimica et Biophysica Acta 2002; 1561(2): 135-146.
73. Petrache HI, Zemb T, Belloni L, Parsegian VA. Salt screening and specific ion adsorption determine neutral-lipid membrane interactions. Proc Natl Acad Sci USA 2006; 103(21): 7982-7987.
74. Victorov AV, Janes N, Taraschi TF, Hoek JB. Packing constraints and electrostatic surface potentials determine transmembrane asymmetry of phosphatidylethanol. Biophysical J 1997; 72(6): 2588-2598.
75. Mellman I, Fuchs R, Helenius A. Acidification of the endocytic and exocytic pathways. Annu Rev Biochem 1986; 55: 663-700.
76. Anderson RG, Pathak RK. Vesicles and cisternae in the trans Golgi apparatus of human fibroblasts are acidic compartments. Cell 1985; 40(3): 635-643.
77. Mellman I. The importance of being acid: The role of acidification in intracellular membrane traffic. J Exp Biol 1992; 172: 39-45.
78. Bayer N, Schober D, Prchla E, Murphy RF, Blaas D, Fuchs R. Effect of bafilomycin A1 and nocodazole on endocytic transport in HeLa cells: Implications for viral uncoating and infection. J Virol 1998; 72(12): 9645-9655.
79. van Deurs B, Holm PK, Sandvig K. Inhibition of the vacuolar H(+)-ATPase with bafilomycin reduces delivery of internalized molecules from mature multivesicular endosomes to lysosomes in HEp-2 cells. Eur J Cell Biol 1996; 69(4): 343-350.
80. Weisz OA. Acidification and protein traffic. Int Rev Cytol 2003; 226: 259-319.
81. Hurtado-Lorenzo A, Skinner M, El Annan J, Futai M, Sun-Wada GH, Bourgoin S, et al. V-ATPase interacts with ARNO and Arf6 in early endosomes and regulates the protein degradative pathway. Nat Cell Biol 2006; 8(2): 124-136.
82. Anbari M, Root KV, Van Dyke RW. Role of Na,K-ATPase in regulating acidification of early rat liver endocytic vesicles. Hepatology 1994; 19(4): 1034-1043.
83. Cain CC, Sipe DM, Murphy RF. Regulation of endocytic pH by the Na+,K+-ATPase in living cells. Proc Natl Acad Sci USA 1989; 86(2): 544-548.
84. Fuchs R, Schmid S, Mellman I. A possible role for Na+,K+-ATPase in regulating ATP-dependent endosome acidification. Proc Natl Acad Sci USA 1989; 86(2): 539-543.
85. Grabe M, Oster G. Regulation of organelle acidity. J Gen Physiol 2001; 117(4): 329-344.
86. Hara-Chikuma M, Wang Y, Guggino SE, Guggino WB, Verkman AS. Impaired acidification in early endosomes of ClC-5 deficient proximal tubule. Biochem Biophys Res Commun 2005; 329(3): 941-946.
87. Hara-Chikuma M, Yang B, Sonawane ND, Sasaki S, Uchida S, Verkman AS. ClC-3 chloride channels facilitate endosomal acidification and chloride accumulation. J Biol Chem 2005; 280(2): 1241-1247.
88. Jentsch TJ. Chloride and the endosomal-lysosomal pathway: emerging roles of CLC chloride transporters. J Physiol 2007; 578(Pt 3): 633-640.
89. Mohammad-Panah R, Harrison R, Dhani S, Ackerley C, Huan LJ, Wang Y, et al. The chloride channel ClC-4 contributes to endosomal acidification and trafficking. J Biol Chem 2003; 278(31): 29267-29277.
90. Di A, Brown ME, Deriy LV, Li C, Szeto FL, Chen Y, et al. CFTR regulates phagosome acidification in macrophages and alters bactericidal activity. Nat Cell Biol 2006; 8(9): 933-944.
91. Schapiro FB, Grinstein S. Determinants of the pH of the Golgi complex. J Biol Chem 2000; 275(28): 21025-21032.
92. Cherny VV, DeCoursey TE. PH-dependent inhibition of voltagegated H(+) currents in rat alveolar epithelial cells by Zn(2+) and other divalent cations. J Gen Physiol 1999; 114(6): 819-838.
93. Wu MM, Grabe M, Adams S, Tsien RY, Moore HP, Machen TE. Mechanisms of pH regulation in the regulated secretory pathway. J Biol Chem 2001; 276(35): 33027-33035.
94. Simon SM, Schindler M. Cell biological mechanisms of multidrug resistance in tumors. Proc Natl Acad Sci USA 1994; 91(9): 3497-3504.
95. Jiang LW, Maher VM, McCormick JJ, Schindler M. Alkalinization of the lysosomes is correlated with ras transformation of murine and human fibroblasts. J Biol Chem 1990; 265(9): 4775-4777.
96. Schindler M, Grabski S, Hoff E, Simon SM. Defective pH regulation of acidic compartments in human breast cancer cells (MCF-7) is normalized in adriamycin-resistant cells (MCF-7adr). Biochemistry 1996; 35(9): 2811-2817.
97. Altan N, Chen Y, Schindler M, Simon SM. Defective acidification in human breast tumor cells and implications for chemotherapy. J Exp Med 1998; 187(10): 1583-1598.
98. Lagadic-Gossmann D, Huc L, Lecureur V. Alterations of intracellular pH homeostasis in apoptosis: origins and roles. Cell Death Differ 2004; 11(9): 953-961.
99. Weigele, M., Dalgarno, D.C., Iuliucci, J., Keenan, T.P., Sawyer, T.K. Proton pump inhibitors. US20020010159 (2002).
100. Boffelli, D., Hauser, H. Amphipathic molecules as cholesterol and other lipid uptake inhibitors. US20010005714 (2001).
101. Mangelsdorf, D.J., Repa, J.J., Turley, S.D., Dietschy, J.M. Compositions and methods of modulating cholesterol metabolism. US6835866 (2004).
102. Giles, I. B. Ionic cancer therapy and methods for using same in the treatment of tumors and metastasis US20040253323 (2004)
103. Gorin, A. F., Nantz, H. M. Amino acid and peptide conjugates of amiloride and methods of use thereof. US7863415 (2010).
104. Uemoto, K., Takayanagi, K., Kazayama, S. Cyclohepta[b]pyridine- 3-carbonylguanidine derivative and pharmaceutical product containing same substituted guanide derivatives. US7875625 (2006).
105. Boyd, R.M., Gustafson, R.K. Chondropsin-class antitumor VATPase inhibitor compounds, compositions and methods of use thereof. US7521475 (2009).
106. Boyd, R.M., Gustafson, R.K. Chondropsin-class antitumor VATPase inhibitor compounds, compositions and methods of use thereof. US7205334 (2009).
107. Paglin, S., Yahalom, J., Hollister, T., Delohery, T. Inhibition of vacuolar proton ATPase activity and/or the modulation of acidic organelle function sensitizes cells to radiation, chemotherapy and biological agents. US6982252 (2001)
108. Sullivan, M., Murray, C.M., Hutchinson, R., Donald, D.K., Jackson, C.G., Jackson, P.J., Bantick, J.R., Cook, I.D. Inhibitors of monocarboxylate transport. US0072746 (2004)
109. Wahl ML, Owen JA, Burd R, Herlands RA, Nogami SS, Rodeck U, et al. Regulation of intracellular pH in human melanoma: Potential therapeutic implications. Mol Cancer Ther 2002; 1(8): 617-628.
110. Sonveaux P, Vegran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest 2008; 118(12): 3930-3942.
111. Pouyssegur J, Franchi A, Pages G. PHi, aerobic glycolysis and vascular endothelial growth factor in tumour growth. Novartis Found Symp 2001; 240: 186-196; discussion 96-8.
112. Scholz W, Albus U, Counillon L, Gogelein H, Lang HJ, Linz W, et al. Protective effects of HOE642, a selective sodium-hydrogen exchange subtype 1 inhibitor, on cardiac ischaemia and reperfusion. Cardiovasc Res 1995; 29(2): 260-268.
113. Moser TL, Stack MS, Asplin I, Enghild JJ, Hojrup P, Everitt L, et al. Angiostatin binds ATP synthase on the surface of human endothelial cells. Proc Natl Acad Sci USA 1999; 96(6): 2811-2816.
114. Moser TL, Kenan DJ, Ashley TA, Roy JA, Goodman MD, Misra UK, et al. Endothelial cell surface F1-F0 ATP synthase is active in ATP synthesis and is inhibited by angiostatin. Proc Natl Acad Sci USA 2001; 98(12): 6656-6661