Gramicidin A: A New Mission for an Old Antibiotic
Main Article Content
Keywords
Gramicidin, ionophore, renal cell carcinoma
Abstract
Gramicidin A (GA) is a channel-forming ionophore that renders biological membranes permeable to specific cations which disrupts cellular ionic homeostasis. It is a well-known antibiotic, however it’s potential as a therapeutic agent for cancer has not been widely evaluated. In two recently published studies, we showed that GA treatment is toxic to cell lines and tumor xenografts derived from renal cell carcinoma (RCC), a devastating disease that is highly resistant to conventional therapy. GA was found to possess the qualities of both a cytotoxic drug and a targeted angiogenesis inhibitor, and this combination significantly compromised RCC growth in vitro and in vivo. In this review, we summarize our recent research on GA, discuss the possible mechanisms whereby it exerts its anti-tumor effects, and share our perspectives on the future opportunities and challenges to the use of GA as a new anticancer agent.
References
1. Kart A, Bilgili A. Ionophore Antibiotics: Toxicity, Mode of Action and Neurotoxic Aspect of Carboxylic Ionophores. Journal of Animal and Veterinary Advances. 2008;7:748-51.
2. Kevin II DA, Meujo DAF, Hamann MT. Polyether ionophores: broad-spectrum and promising biologically active molecules for the control of drug-resistant bacteria and parasites. Expert Opinion on Drug Discovery. 2009;4:109-46. Doi: http://dx.doi.org/10.1517/17460440802661443
3. Huczynski A. Polyether ionophores-promising bioactive molecules for cancer therapy. Bioorg Med Chem Lett. 2012;22:7002-10. Doi: http://dx.doi.org/10.1016/j.bmcl.2012.09.046
4. Naujokat C, Steinhart R. Salinomycin as a drug for targeting human cancer stem cells. J Biomed Biotechnol. 2012;2012:950658. Doi: http://dx.doi.org/10.1155/2012/950658
5. Zhou S, Wang F, Wong ET, Fonkem E, Hsieh TC, Wu JM, Wu E. Salinomycin: a novel anti-cancer agent with known anti-coccidial activities. Current medicinal chemistry. 2013;20:4095-101. Doi: http://dx.doi.org/10.2174/15672050113109990199
6. Kelkar DA, Chattopadhyay A. The gramicidin ion channel: a model membrane protein. Biochim Biophys Acta. 2007;1768:2011-25. Doi: http://dx.doi.org/10.1016/j.bbamem.2007.05.011
7. Wang F, Qin L, Pace CJ, Wong P, Malonis R, Gao J. Solubilized gramicidin A as potential systemic antibiotics. Chembiochem. 2012;13:51-5. Doi: http://dx.doi.org/10.1002/cbic.201100671
8. Otten-Kuipers MA, Beumer TL, Kronenburg NA, Roelofsen B, Op den Kamp JA. Effects of gramicidin and tryptophan-N-formylated gramicidin on the sodium and potassium content of human erythrocytes. Mol Membr Biol. 1996;13:225-32. Doi: http://dx.doi.org/10.3109/09687689609160600
9. Dubos RJ. Studies on a Bactericidal Agent Extracted from a Soil Bacillus : I. Preparation of the Agent. Its Activity in Vitro. J Exp Med. 1939;70:1-10. Doi: http://dx.doi.org/10.1084/jem.70.1.1
10. Dubos RJ, Hotchkiss RD. The Production of Bactericidal Substances by Aerobic Sporulating Bacilli. J Exp Med. 1941;73:629-40. Doi: http://dx.doi.org/10.1084/jem.73.5.629
11. Bourinbaiar AS, Coleman CF. The effect of gramicidin, a topical contraceptive and antimicrobial agent with anti-HIV activity, against herpes simplex viruses type 1 and 2 in vitro. Arch Virol. 1997;142:2225-35. Doi: http://dx.doi.org/10.1007/s007050050237
12. Moll GN, van den Eertwegh V, Tournois H, Roelofsen B, Op den Kamp JA, van Deenen LL. Growth inhibition of Plasmodium falciparum in in vitro cultures by selective action of tryptophan-N-formylated gramicidin incorporated in lipid vesicles. Biochim Biophys Acta. 1991;1062:206-10. Doi: http://dx.doi.org/10.1016/0005-2736(91)90394-N
13. David JM, Owens TA, Barwe SP, Rajasekaran AK. Gramicidin A induces metabolic dysfunction and energy depletion leading to cell death in renal cell carcinoma cells. Mol Cancer Ther. 2013;12:2296-307.
Doi: http://dx.doi.org/10.1158/1535-7163.MCT-13-0445
14. Baldewijns MM, van Vlodrop IJ, Schouten LJ, Soetekouw PM, de Bruine AP, van Engeland M. Genetics and epigenetics of renal cell cancer. Biochim Biophys Acta. 2008;1785:133-55. Doi: http://dx.doi.org/10.1016/j.bbcan.2007.12.002
15. Patard JJ, et al. Prognostic value of histologic subtypes in renal cell carcinoma: a multicenter experience. J Clin Oncol. 2005;23:2763-71. Doi: http://dx.doi.org/10.1200/JCO.2005.07.055
16. Ketola K, Vainio P, Fey V, Kallioniemi O, Iljin K. Monensin is a potent inducer of oxidative stress and inhibitor of androgen signaling leading to apoptosis in prostate cancer cells. Mol Cancer Ther. 2010;9:3175-85. Doi: http://dx.doi.org/10.1158/1535-7163.MCT-10-0368
17. Ketola K, Hilvo M, Hyotylainen T, Vuoristo A, Ruskeepaa AL, Oresic M, Kallioniemi O, Iljin K. Salinomycin inhibits prostate cancer growth and migration via induction of oxidative stress. Br J Cancer. 2012;106:99-106. Doi: http://dx.doi.org/10.1038/bjc.2011.530
18. Kim KY, Yu SN, Lee SY, Chun SS, Choi YL, Park YM, Song CS, Chatterjee B, Ahn SC. Salinomycin-induced apoptosis of human prostate cancer cells due to accumulated reactive oxygen species and mitochondrial membrane depolarization. Biochem Biophys Res Commun. 2011;413:80-6. Doi: http://dx.doi.org/10.1016/j.bbrc.2011.08.054
19. Verdoodt B, Vogt M, Schmitz I, Liffers ST, Tannapfel A, Mirmohammadsadegh A. Salinomycin induces autophagy in colon and breast cancer cells with concomitant generation of reactive oxygen species. PLoS One. 2012;7:e44132. Doi: http://dx.doi.org/10.1371/journal.pone.0044132
20. Jeon SM, Chandel NS, Hay N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature. 2012;485:661-5. Doi: http://dx.doi.org/10.1038/nature11066
21. Wu SB, Wei YH. AMPK-mediated increase of glycolysis as an adaptive response to oxidative stress in human cells: implication of the cell survival in mitochondrial diseases. Biochim Biophys Acta. 2012;1822:233-47. Doi: http://dx.doi.org/10.1016/j.bbadis.2011.09.014
22. Ying W, Alano CC, Garnier P, Swanson RA. NAD+ as a metabolic link between DNA damage and cell death. J Neurosci Res. 2005;79:216-23. Doi: http://dx.doi.org/10.1002/jnr.20289
23. Zong WX, Ditsworth D, Bauer DE, Wang ZQ, Thompson CB. Alkylating DNA damage stimulates a regulated form of necrotic cell death. Genes Dev. 2004;18:1272-82. Doi: http://dx.doi.org/10.1101/gad.1199904
24. Semenza GL. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene. 2010;29:625-34. Doi: http://dx.doi.org/10.1038/onc.2009.441
25. Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW. Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res. 1999;59:5830-5. [PMid:10582706].
26. Talks KL, Turley H, Gatter KC, Maxwell PH, Pugh CW, Ratcliffe PJ, Harris AL. The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol. 2000;157:411-21. Doi: http://dx.doi.org/10.1016/S0002-9440(10)64554-3
27. Haase VH. Renal cancer: Oxygen meets metabolism. Exp Cell Res. 2012. Doi: http://dx.doi.org/10.1016/j.yexcr.2012.02.026
28. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995;92:5510-4. Doi: http://dx.doi.org/10.1073/pnas.92.12.5510
29. Kirchner H, Strumberg D, Bahl A, Overkamp F. Patient-based strategy for systemic treatment of metastatic renal cell carcinoma. Expert Rev Anticancer Ther. 2010;10:585-96. Doi: http://dx.doi.org/10.1586/era.10.25
30. Hahnfeldt P, Folkman J, Hlatky L. Minimizing long-term tumor burden: the logic for metronomic chemotherapeutic dosing and its antiangiogenic basis. Journal of theoretical biology. 2003;220:545-54. Doi: http://dx.doi.org/10.1006/jtbi.2003.3162
31. Christensen HN. Biological Transport. Reading, MA: W. A. Benjamin; 1975
32. Rose M.C. HRW. Stability of sodium and potassium complexes of valinomycin. Biochimica et Biophysica Acta. 1974;372:426-35. Doi: http://dx.doi.org/10.1016/0304-4165(74)90204-9
33. Kamura T, Brower CS, Conaway RC, Conaway JW. A molecular basis for stabilization of the von Hippel-Lindau (VHL) tumor suppressor protein by components of the VHL ubiquitin ligase. J Biol Chem. 2002;277:30388-93. Doi: http://dx.doi.org/10.1074/jbc.M203344200
34. Jung CR, Hwang KS, Yoo J, Cho WK, Kim JM, Kim WH, Im DS. E2-EPF UCP targets pVHL for degradation and associates with tumor growth and metastasis. Nat Med. 2006;12:809-16. Doi: http://dx.doi.org/10.1038/nm1440
35. Ampofo E, Kietzmann T, Zimmer A, Jakupovic M, Montenarh M, Gotz C. Phosphorylation of the von Hippel-Lindau protein (VHL) by protein kinase CK2 reduces its protein stability and affects p53 and HIF-1alpha mediated transcription. Int J Biochem Cell Biol. 2010;42:1729-35. Doi: http://dx.doi.org/10.1016/j.biocel.2010.07.008
36. Kim DS, et al. Cancer cells promote survival through depletion of the von Hippel-Lindau tumor suppressor by protein crosslinking. Oncogene. 2011;30:4780-90. Doi: http://dx.doi.org/10.1038/onc.2011.183
37. Gnarra JR, Tory K, Weng Y, Schmidt L, Wei MH, Li H, Latif F, Liu S, Chen F, Duh FM. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet. 1994;7:85-90. Doi: http://dx.doi.org/10.1038/ng0594-85
38. Schoenfeld A, Davidowitz EJ, Burk RD. A second major native von Hippel-Lindau gene product, initiated from an internal translation start site, functions as a tumor suppressor. Proc Natl Acad Sci U S A. 1998;95:8817-22. Doi: http://dx.doi.org/10.1073/pnas.95.15.8817
39. Jonasch E, et al. State-of-the-science: An update on renal cell carcinoma. Mol Cancer Res. 2012. Doi: http://dx.doi.org/10.1158/1541-7786.MCR-12-0117
40. Nyhan MJ, O'Sullivan GC, McKenna SL. Role of the VHL (von Hippel-Lindau) gene in renal cancer: a multifunctional tumour suppressor. Biochem Soc Trans. 2008;36:472-8. Doi: http://dx.doi.org/10.1042/BST0360472
41. Chitalia VC, et al. Jade-1 inhibits Wnt signalling by ubiquitylating beta-catenin and mediates Wnt pathway inhibition by pVHL. Nat Cell Biol. 2008;10:1208-16. Doi: http://dx.doi.org/10.1038/ncb1781
42. Grayson ML. Kucers' the use of antibiotics : a clinical review of antibacterial, antifungal, antiparasitic and antiviral drugs (6th ed). London: Hodder Arnold; 2010.
43. Boehmerle W, Endres M. Salinomycin induces calpain and cytochrome c-mediated neuronal cell death. Cell Death Dis. 2011;2:e168. Doi: http://dx.doi.org/10.1038/cddis.2011.46
44. Fuchs D, Heinold A, Opelz G, Daniel V, Naujokat C. Salinomycin induces apoptosis and overcomes apoptosis resistance in human cancer cells. Biochem Biophys Res Commun. 2009;390:743-9.
Doi: http://dx.doi.org/10.1016/j.bbrc.2009.10.042
45. Lu D, Choi MY, Yu J, Castro JE, Kipps TJ, Carson DA. Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells. Proc Natl Acad Sci U S A. 2011;108:13253-7.
Doi: http://dx.doi.org/10.1073/pnas.1110431108
46. Park WH, Lee MS, Park K, Kim ES, Kim BK, Lee YY. Monensin-mediated growth inhibition in acute myelogenous leukemia cells via cell cycle arrest and apoptosis. Int J Cancer. 2002;101:235-42. Doi: http://dx.doi.org/10.1002/ijc.10592
47. Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA, Lander ES. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009;138:645-59. Doi: http://dx.doi.org/10.1016/j.cell.2009.06.034
48. Basu D, et al. Detecting and targeting mesenchymal-like subpopulations within squamous cell carcinomas. Cell Cycle. 2011;10:2008-16. Doi: http://dx.doi.org/10.4161/cc.10.12.15883
49. Tang QL, et al. Salinomycin inhibits osteosarcoma by targeting its tumor stem cells. Cancer Lett. 2011;311:113-21. Doi: http://dx.doi.org/10.1016/j.canlet.2011.07.016
50. Zhang B, Wang X, Cai F, Chen W, Loesch U, Bitzer J, Zhong XY. Effects of salinomycin on human ovarian cancer cell line OV2008 are associated with modulating p38 MAPK. Tumour Biol. 2012.
Doi: http://dx.doi.org/10.1007/s13277-012-0445-9
51. Sorochkina AI, Plotnikov EY, Rokitskaya TI, Kovalchuk SI, Kotova EA, Sychev SV, Zorov DB, Antonenko YN. N-terminally glutamate-substituted analogue of gramicidin A as protonophore and selective mitochondrial uncoupler. PLoS One. 2012;7:e41919. Doi: http://dx.doi.org/10.1371/journal.pone.0041919
52. Lewis JC, Dimick KP, Feustel IC, Fevold HL, Olcott HS, Fraenkel-Conrat H. Modification of Gramicidin through Reaction with Formaldehyde. Science. 1945;102:274-5. Doi: http://dx.doi.org/10.1126/science.102.2646.274
53. Wijesinghe D, Arachchige MC, Lu A, Reshetnyak YK, Andreev OA. pH dependent transfer of nano-pores into membrane of cancer cells to induce apoptosis. Scientific reports. 2013;3:3560. Doi: http://dx.doi.org/10.1038/srep03560
2. Kevin II DA, Meujo DAF, Hamann MT. Polyether ionophores: broad-spectrum and promising biologically active molecules for the control of drug-resistant bacteria and parasites. Expert Opinion on Drug Discovery. 2009;4:109-46. Doi: http://dx.doi.org/10.1517/17460440802661443
3. Huczynski A. Polyether ionophores-promising bioactive molecules for cancer therapy. Bioorg Med Chem Lett. 2012;22:7002-10. Doi: http://dx.doi.org/10.1016/j.bmcl.2012.09.046
4. Naujokat C, Steinhart R. Salinomycin as a drug for targeting human cancer stem cells. J Biomed Biotechnol. 2012;2012:950658. Doi: http://dx.doi.org/10.1155/2012/950658
5. Zhou S, Wang F, Wong ET, Fonkem E, Hsieh TC, Wu JM, Wu E. Salinomycin: a novel anti-cancer agent with known anti-coccidial activities. Current medicinal chemistry. 2013;20:4095-101. Doi: http://dx.doi.org/10.2174/15672050113109990199
6. Kelkar DA, Chattopadhyay A. The gramicidin ion channel: a model membrane protein. Biochim Biophys Acta. 2007;1768:2011-25. Doi: http://dx.doi.org/10.1016/j.bbamem.2007.05.011
7. Wang F, Qin L, Pace CJ, Wong P, Malonis R, Gao J. Solubilized gramicidin A as potential systemic antibiotics. Chembiochem. 2012;13:51-5. Doi: http://dx.doi.org/10.1002/cbic.201100671
8. Otten-Kuipers MA, Beumer TL, Kronenburg NA, Roelofsen B, Op den Kamp JA. Effects of gramicidin and tryptophan-N-formylated gramicidin on the sodium and potassium content of human erythrocytes. Mol Membr Biol. 1996;13:225-32. Doi: http://dx.doi.org/10.3109/09687689609160600
9. Dubos RJ. Studies on a Bactericidal Agent Extracted from a Soil Bacillus : I. Preparation of the Agent. Its Activity in Vitro. J Exp Med. 1939;70:1-10. Doi: http://dx.doi.org/10.1084/jem.70.1.1
10. Dubos RJ, Hotchkiss RD. The Production of Bactericidal Substances by Aerobic Sporulating Bacilli. J Exp Med. 1941;73:629-40. Doi: http://dx.doi.org/10.1084/jem.73.5.629
11. Bourinbaiar AS, Coleman CF. The effect of gramicidin, a topical contraceptive and antimicrobial agent with anti-HIV activity, against herpes simplex viruses type 1 and 2 in vitro. Arch Virol. 1997;142:2225-35. Doi: http://dx.doi.org/10.1007/s007050050237
12. Moll GN, van den Eertwegh V, Tournois H, Roelofsen B, Op den Kamp JA, van Deenen LL. Growth inhibition of Plasmodium falciparum in in vitro cultures by selective action of tryptophan-N-formylated gramicidin incorporated in lipid vesicles. Biochim Biophys Acta. 1991;1062:206-10. Doi: http://dx.doi.org/10.1016/0005-2736(91)90394-N
13. David JM, Owens TA, Barwe SP, Rajasekaran AK. Gramicidin A induces metabolic dysfunction and energy depletion leading to cell death in renal cell carcinoma cells. Mol Cancer Ther. 2013;12:2296-307.
Doi: http://dx.doi.org/10.1158/1535-7163.MCT-13-0445
14. Baldewijns MM, van Vlodrop IJ, Schouten LJ, Soetekouw PM, de Bruine AP, van Engeland M. Genetics and epigenetics of renal cell cancer. Biochim Biophys Acta. 2008;1785:133-55. Doi: http://dx.doi.org/10.1016/j.bbcan.2007.12.002
15. Patard JJ, et al. Prognostic value of histologic subtypes in renal cell carcinoma: a multicenter experience. J Clin Oncol. 2005;23:2763-71. Doi: http://dx.doi.org/10.1200/JCO.2005.07.055
16. Ketola K, Vainio P, Fey V, Kallioniemi O, Iljin K. Monensin is a potent inducer of oxidative stress and inhibitor of androgen signaling leading to apoptosis in prostate cancer cells. Mol Cancer Ther. 2010;9:3175-85. Doi: http://dx.doi.org/10.1158/1535-7163.MCT-10-0368
17. Ketola K, Hilvo M, Hyotylainen T, Vuoristo A, Ruskeepaa AL, Oresic M, Kallioniemi O, Iljin K. Salinomycin inhibits prostate cancer growth and migration via induction of oxidative stress. Br J Cancer. 2012;106:99-106. Doi: http://dx.doi.org/10.1038/bjc.2011.530
18. Kim KY, Yu SN, Lee SY, Chun SS, Choi YL, Park YM, Song CS, Chatterjee B, Ahn SC. Salinomycin-induced apoptosis of human prostate cancer cells due to accumulated reactive oxygen species and mitochondrial membrane depolarization. Biochem Biophys Res Commun. 2011;413:80-6. Doi: http://dx.doi.org/10.1016/j.bbrc.2011.08.054
19. Verdoodt B, Vogt M, Schmitz I, Liffers ST, Tannapfel A, Mirmohammadsadegh A. Salinomycin induces autophagy in colon and breast cancer cells with concomitant generation of reactive oxygen species. PLoS One. 2012;7:e44132. Doi: http://dx.doi.org/10.1371/journal.pone.0044132
20. Jeon SM, Chandel NS, Hay N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature. 2012;485:661-5. Doi: http://dx.doi.org/10.1038/nature11066
21. Wu SB, Wei YH. AMPK-mediated increase of glycolysis as an adaptive response to oxidative stress in human cells: implication of the cell survival in mitochondrial diseases. Biochim Biophys Acta. 2012;1822:233-47. Doi: http://dx.doi.org/10.1016/j.bbadis.2011.09.014
22. Ying W, Alano CC, Garnier P, Swanson RA. NAD+ as a metabolic link between DNA damage and cell death. J Neurosci Res. 2005;79:216-23. Doi: http://dx.doi.org/10.1002/jnr.20289
23. Zong WX, Ditsworth D, Bauer DE, Wang ZQ, Thompson CB. Alkylating DNA damage stimulates a regulated form of necrotic cell death. Genes Dev. 2004;18:1272-82. Doi: http://dx.doi.org/10.1101/gad.1199904
24. Semenza GL. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene. 2010;29:625-34. Doi: http://dx.doi.org/10.1038/onc.2009.441
25. Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW. Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res. 1999;59:5830-5. [PMid:10582706].
26. Talks KL, Turley H, Gatter KC, Maxwell PH, Pugh CW, Ratcliffe PJ, Harris AL. The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol. 2000;157:411-21. Doi: http://dx.doi.org/10.1016/S0002-9440(10)64554-3
27. Haase VH. Renal cancer: Oxygen meets metabolism. Exp Cell Res. 2012. Doi: http://dx.doi.org/10.1016/j.yexcr.2012.02.026
28. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995;92:5510-4. Doi: http://dx.doi.org/10.1073/pnas.92.12.5510
29. Kirchner H, Strumberg D, Bahl A, Overkamp F. Patient-based strategy for systemic treatment of metastatic renal cell carcinoma. Expert Rev Anticancer Ther. 2010;10:585-96. Doi: http://dx.doi.org/10.1586/era.10.25
30. Hahnfeldt P, Folkman J, Hlatky L. Minimizing long-term tumor burden: the logic for metronomic chemotherapeutic dosing and its antiangiogenic basis. Journal of theoretical biology. 2003;220:545-54. Doi: http://dx.doi.org/10.1006/jtbi.2003.3162
31. Christensen HN. Biological Transport. Reading, MA: W. A. Benjamin; 1975
32. Rose M.C. HRW. Stability of sodium and potassium complexes of valinomycin. Biochimica et Biophysica Acta. 1974;372:426-35. Doi: http://dx.doi.org/10.1016/0304-4165(74)90204-9
33. Kamura T, Brower CS, Conaway RC, Conaway JW. A molecular basis for stabilization of the von Hippel-Lindau (VHL) tumor suppressor protein by components of the VHL ubiquitin ligase. J Biol Chem. 2002;277:30388-93. Doi: http://dx.doi.org/10.1074/jbc.M203344200
34. Jung CR, Hwang KS, Yoo J, Cho WK, Kim JM, Kim WH, Im DS. E2-EPF UCP targets pVHL for degradation and associates with tumor growth and metastasis. Nat Med. 2006;12:809-16. Doi: http://dx.doi.org/10.1038/nm1440
35. Ampofo E, Kietzmann T, Zimmer A, Jakupovic M, Montenarh M, Gotz C. Phosphorylation of the von Hippel-Lindau protein (VHL) by protein kinase CK2 reduces its protein stability and affects p53 and HIF-1alpha mediated transcription. Int J Biochem Cell Biol. 2010;42:1729-35. Doi: http://dx.doi.org/10.1016/j.biocel.2010.07.008
36. Kim DS, et al. Cancer cells promote survival through depletion of the von Hippel-Lindau tumor suppressor by protein crosslinking. Oncogene. 2011;30:4780-90. Doi: http://dx.doi.org/10.1038/onc.2011.183
37. Gnarra JR, Tory K, Weng Y, Schmidt L, Wei MH, Li H, Latif F, Liu S, Chen F, Duh FM. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet. 1994;7:85-90. Doi: http://dx.doi.org/10.1038/ng0594-85
38. Schoenfeld A, Davidowitz EJ, Burk RD. A second major native von Hippel-Lindau gene product, initiated from an internal translation start site, functions as a tumor suppressor. Proc Natl Acad Sci U S A. 1998;95:8817-22. Doi: http://dx.doi.org/10.1073/pnas.95.15.8817
39. Jonasch E, et al. State-of-the-science: An update on renal cell carcinoma. Mol Cancer Res. 2012. Doi: http://dx.doi.org/10.1158/1541-7786.MCR-12-0117
40. Nyhan MJ, O'Sullivan GC, McKenna SL. Role of the VHL (von Hippel-Lindau) gene in renal cancer: a multifunctional tumour suppressor. Biochem Soc Trans. 2008;36:472-8. Doi: http://dx.doi.org/10.1042/BST0360472
41. Chitalia VC, et al. Jade-1 inhibits Wnt signalling by ubiquitylating beta-catenin and mediates Wnt pathway inhibition by pVHL. Nat Cell Biol. 2008;10:1208-16. Doi: http://dx.doi.org/10.1038/ncb1781
42. Grayson ML. Kucers' the use of antibiotics : a clinical review of antibacterial, antifungal, antiparasitic and antiviral drugs (6th ed). London: Hodder Arnold; 2010.
43. Boehmerle W, Endres M. Salinomycin induces calpain and cytochrome c-mediated neuronal cell death. Cell Death Dis. 2011;2:e168. Doi: http://dx.doi.org/10.1038/cddis.2011.46
44. Fuchs D, Heinold A, Opelz G, Daniel V, Naujokat C. Salinomycin induces apoptosis and overcomes apoptosis resistance in human cancer cells. Biochem Biophys Res Commun. 2009;390:743-9.
Doi: http://dx.doi.org/10.1016/j.bbrc.2009.10.042
45. Lu D, Choi MY, Yu J, Castro JE, Kipps TJ, Carson DA. Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells. Proc Natl Acad Sci U S A. 2011;108:13253-7.
Doi: http://dx.doi.org/10.1073/pnas.1110431108
46. Park WH, Lee MS, Park K, Kim ES, Kim BK, Lee YY. Monensin-mediated growth inhibition in acute myelogenous leukemia cells via cell cycle arrest and apoptosis. Int J Cancer. 2002;101:235-42. Doi: http://dx.doi.org/10.1002/ijc.10592
47. Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA, Lander ES. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009;138:645-59. Doi: http://dx.doi.org/10.1016/j.cell.2009.06.034
48. Basu D, et al. Detecting and targeting mesenchymal-like subpopulations within squamous cell carcinomas. Cell Cycle. 2011;10:2008-16. Doi: http://dx.doi.org/10.4161/cc.10.12.15883
49. Tang QL, et al. Salinomycin inhibits osteosarcoma by targeting its tumor stem cells. Cancer Lett. 2011;311:113-21. Doi: http://dx.doi.org/10.1016/j.canlet.2011.07.016
50. Zhang B, Wang X, Cai F, Chen W, Loesch U, Bitzer J, Zhong XY. Effects of salinomycin on human ovarian cancer cell line OV2008 are associated with modulating p38 MAPK. Tumour Biol. 2012.
Doi: http://dx.doi.org/10.1007/s13277-012-0445-9
51. Sorochkina AI, Plotnikov EY, Rokitskaya TI, Kovalchuk SI, Kotova EA, Sychev SV, Zorov DB, Antonenko YN. N-terminally glutamate-substituted analogue of gramicidin A as protonophore and selective mitochondrial uncoupler. PLoS One. 2012;7:e41919. Doi: http://dx.doi.org/10.1371/journal.pone.0041919
52. Lewis JC, Dimick KP, Feustel IC, Fevold HL, Olcott HS, Fraenkel-Conrat H. Modification of Gramicidin through Reaction with Formaldehyde. Science. 1945;102:274-5. Doi: http://dx.doi.org/10.1126/science.102.2646.274
53. Wijesinghe D, Arachchige MC, Lu A, Reshetnyak YK, Andreev OA. pH dependent transfer of nano-pores into membrane of cancer cells to induce apoptosis. Scientific reports. 2013;3:3560. Doi: http://dx.doi.org/10.1038/srep03560
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Published
Jan 18, 2015
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Gramicidin A: A New Mission for an Old Antibiotic. (2015). Journal of Kidney Cancer, 2(1), 15-24. https://doi.org/10.15586/jkcvhl.2015.21
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Kidney Cancer: Review Articles
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How to Cite
Gramicidin A: A New Mission for an Old Antibiotic. (2015). Journal of Kidney Cancer, 2(1), 15-24. https://doi.org/10.15586/jkcvhl.2015.21