title: Signaling pathways of ESE-16, an antimitotic and anticarbonic anhydrase estradiol analog, in breast cancer cells.
abstract: The aim of this study was to characterize the in vitro action of 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10)16-tetraene (ESE-16) on non-tumorigenic MCF-12A, tumorigenic MCF-7 and metastatic MDA-MB-231 breast cancer cells. ESE-16 is able to inhibit the activity of a carbonic anhydrase II and a mimic of carbonic anhydrase IX in the nanomolar range. Gene and protein expression studies using various techniques including gene and antibody microarrays and various flow cytometry assays yielded valuable information about the mechanism of action of ESE-16. The JNK pathway was identified as an important pathway mediating the effects of ESE-16 while the p38 stress-induced pathway is more important in MDA-MB-231 cells exposed to ESE-16. Lysosomal rupture and iron metabolism was identified as important mediators of mitochondrial membrane depolarization. Abrogation of Bcl-2 phosphorylation status as a result of ESE-16 also plays a role in inducing mitochondrial membrane depolarization. The study provides a basis for future research projects to develop the newly synthesized compound into a clinically usable anticancer agent either alone or in combination with other agents.
  
  
  BACKGROUND
  Antimitotic, anticarbonic anhydrase IX, apoptosis, autophagy, cell cycle arrest, Bcl-2, JNK, p38, mitochondrial membrane depolarization, flow cytometry, gene expression and protein microarray, anticancer.
authors: Department of Physiology, University of Pretoria, Pretoria, Gauteng, South Africa. standerandre@gmail.com
authors: Barend Andre
authors: BA
authors: Stander
authors: Fourie
authors: F
authors: Joubert
authors: Chingkuang
authors: C
authors: Tu
authors: Katherine H
authors: KH
authors: Sippel
authors: Robert
authors: R
authors: McKenna
authors: Annie Margaretha
authors: AM
authors: Joubert
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D061986:MCF-7 Cells; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D004958:Estradiol; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D024402:Carbonic Anhydrase II
references: Mol Biol Cell. 2008 Apr;19(4):1798-813
references: 18199686
references: J Mol Signal. 2008 Sep 12;3:15
references: 18789159
references: Mech Ageing Dev. 2007 Jan;128(1):161-7
references: 17126887
references: Antioxid Redox Signal. 2007 Dec;9(12):2277-93
references: 17979528
references: J Biol Chem. 2002 Apr 12;277(15):12622-31
references: 11812785
references: Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6286-91
references: 11959917
references: Br J Cancer. 2004 Feb 23;90(4):932-7
references: 14970876
references: Crit Rev Clin Lab Sci. 2008;45(1):1-23
references: 18293179
references: Bioorg Med Chem Lett. 2009 Nov 1;19(21):6241-4
references: 19782564
references: Free Radic Biol Med. 2009 Jul 1;47(1):1-12
references: 19362144
references: J Chromatogr B Analyt Technol Biomed Life Sci. 2003 Nov 25;797(1-2):229-40
references: 14630152
references: Am J Physiol Heart Circ Physiol. 2000 Dec;279(6):H2889-97
references: 11087245
references: J Steroid Biochem Mol Biol. 2010 Apr;119(3-5):149-60
references: 20193762
references: Redox Rep. 2002;7(1):55-7; author reply 59-60
references: 11981456
references: Invest New Drugs. 2011 Apr;29(2):340-6
references: 20084425
references: Oncogene. 2008 Oct 27;27(50):6434-51
references: 18955971
references: Cancer Res. 2004 Sep 1;64(17):6160-5
references: 15342400
references: Blood. 2002 May 15;99(10):3505-16
references: 11986201
references: Crit Rev Oncog. 2011;16(1-2):129-40
references: 22150313
references: Mol Cancer Ther. 2008 Jun;7(6):1472-82
references: 18566218
references: Oncol Rep. 1999 Jan-Feb;6(1):33-7
references: 9864397
references: Mol Cancer Ther. 2010 May;9(5):1408-18
references: 20442304
references: Free Radic Biol Med. 2010 May 15;48(10):1347-57
references: 20172024
references: Bioorg Med Chem. 2007 Jul 1;15(13):4336-50
references: 17475500
references: Recent Pat Antiinfect Drug Discov. 2009 Nov;4(3):164-82
references: 19673697
references: Curr Opin Cell Biol. 2002 Dec;14(6):706-14
references: 12473343
references: BMC Cancer. 2008 Jul 23;8:206
references: 18651980
references: Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):19878-83
references: 19903888
references: Oncogene. 2008 Dec;27 Suppl 1:S71-83
references: 19641508
references: Curr Mol Med. 2008 Mar;8(2):102-18
references: 18336291
references: Methods Enzymol. 1982;87:732-52
references: 6294458
references: Methods Mol Biol. 2008;477:89-97
references: 19082941
references: Breast Cancer Res Treat. 2011 Feb;126(1):63-71
references: 20390345
references: Biochemistry. 2009 Feb 17;48(6):1322-31
references: 19170619
references: Cell Biochem Funct. 2008 Sep-Oct;26(5):632-42
references: 18508385
references: Cancer Res. 2006 Jul 1;66(13):6699-707
references: 16818644
references: Biochem J. 2010 May 13;428(2):183-90
references: 20331437
references: Free Radic Biol Med. 2012 Jan 1;52(1):7-18
references: 22019631
references: J Cell Biochem. 2004 Oct 1;93(2):242-50
references: 15368352
references: Cell Mol Life Sci. 2007 Mar;64(5):589-600
references: 17334950
references: Exp Cell Res. 2006 Jul 1;312(11):1950-60
references: 16603154
references: J Cell Biol. 2004 May 10;165(3):347-56
references: 15123740
references: Pharmacol Ther. 2001 Oct;92(1):57-70
references: 11750036
references: Mol Interv. 2011 Apr;11(2):141-50
references: 21540474
references: Biochem Biophys Res Commun. 1996 Nov 12;228(2):467-73
references: 8920936
references: Nat Rev Mol Cell Biol. 2006 Sep;7(9):644-56
references: 16896351
references: Annu Rev Genet. 2003;37:251-82
references: 14616062
references: J Cell Biochem. 2007 Jul 1;101(4):937-49
references: 17171643
references: Cancer Invest. 2009 Jul;27(6):613-23
references: 19367501
references: J Exp Med. 2003 May 19;197(10):1323-34
references: 12756268
references: Free Radic Biol Med. 2001 Aug 15;31(4):490-8
references: 11498282
references: Cell Death Differ. 2004 Apr;11(4):381-9
references: 14685163
references: Mol Cancer Ther. 2011 May;10(5):874-82
references: 21422268
references: Arch Immunol Ther Exp (Warsz). 2002;50(1):19-34
references: 11916306
references: Int J Oncol. 1999 Oct;15(4):639-46
references: 10493943
references: Proc Natl Acad Sci U S A. 1989 Jan;86(1):99-103
references: 2911585
references: Annu Rev Biochem. 1995;64:375-401
references: 7574487
references: BJU Int. 2008 Jun;101 Suppl 4:8-15
references: 18430116
references: J Cancer Res Clin Oncol. 2012 Aug;138(8):1279-89
references: 22447040
references: Free Radic Biol Med. 2003 May 15;34(10):1243-52
references: 12726912
references: Cancer Res. 2006 Jan 1;66(1):212-20
references: 16397234
references: Semin Cancer Biol. 2006 Dec;16(6):427-35
references: 17081769
references: Chem Biol Drug Des. 2011 Mar;77(3):173-81
references: 21244635
references: Cancer Res. 2006 Jan 1;66(1):324-30
references: 16397246