title: Effects of ellipticine on ALDH1A1-expressing breast cancer stem cells--an in vitro and in silico study.
abstract: Targeting breast cancer stem cells (BCSCs) offers a promising strategy for breast cancer treatment. We examined the plant alkaloid ellipticine for its efficacy to inhibit the expression of aldehyde dehydrogenase 1 class A1 (ALDH1A1)-positive BCSCs by in vitro and in silico methods. At 3 mM concentration, ellipticine decreased the expression of ALDH1A1-positive BCSCs by 62% (p = 0.073) in the MCF7 cell line and by 53% (p = 0.024) in the SUM159 cell line compared to vehicle-treated cultures. Ellipticine significantly reduced the formation of mammospheres, whereas paclitaxel enhanced mammosphere formation in both the treated cell lines. Interestingly, when treated with a combination of ellipticine and paclitaxel, the percentage of ALDH1A1-positive BCSCs dropped by several fold in vitro. A homology model of Homo sapiens ALDH1A1 was built using the crystal structure of NAD-bound sheep liver class I aldehyde dehydrogenase [PDB ID: 1BXS] as a template. Molecular simulation and docking studies revealed that the amino acids Asn-117 and Asn-121, Glu-249, Cys-302, and Gln-350, present in the active site of human ALDH1A1, played a vital role in interacting with the drug. The present study suggests that ellipticine reduces the proliferation and self-renewal ability of ALDH1A1-positive BCSCs and can be used in combination with a cytotoxic drug like paclitaxel for potential targeting of BCSCs.
authors: Tumour Biology Laboratory, National Institute of Pathology (ICMR), Safdarjung Hospital Campus, New Delhi, 110029, India.
authors: Santhi Latha
authors: SL
authors: Pandrangi
authors: Rajasekhar
authors: R
authors: Chikati
authors: Pradeep Singh
authors: PS
authors: Chauhan
authors: Chitta Suresh
authors: CS
authors: Kumar
authors: Anropa
authors: A
authors: Banarji
authors: Sunita
authors: S
authors: Saxena
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000080924:Aldehyde Dehydrogenase 1 Family; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004611:Ellipticines / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D050697:Retinal Dehydrogenase; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004611:Ellipticines; C034192:ellipticine; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase; D017239:Paclitaxel
references: Bull Cancer. 1981;68(3):224-31
references: 7039729
references: J Cell Mol Med. 2009 Aug;13(8B):2236-2252
references: 18681906
references: Chem Biol Interact. 2009 Mar 16;178(1-3):48-55
references: 18952074
references: Cancer Res. 2004 Nov 15;64(22):8374-80
references: 15548707
references: Mol Pharmacol. 1992 Oct;42(4):590-5
references: 1331751
references: Jpn J Cancer Res. 1995 Sep;86(9):819-27
references: 7591958
references: Cell Prolif. 2003 Oct;36 Suppl 1:59-72
references: 14521516
references: Genes Dev. 2003 May 15;17(10):1253-70
references: 12756227
references: Cell. 2008 Jul 11;134(1):62-73
references: 18614011
references: Oncogene. 2003 Jul 17;22(29):4478-87
references: 12881704
references: Mol Cancer Ther. 2008 Mar;7(3):500-9
references: 18319333
references: PLoS Biol. 2009 Jun 2;7(6):e1000121
references: 19492080
references: Science. 1991 Jul 12;253(5016):164-70
references: 1853201
references: Pathobiology. 2008;75(2):75-84
references: 18544962
references: Cell. 2007 Dec 14;131(6):1109-23
references: 18083101
references: Electrophoresis. 1997 Dec;18(15):2714-23
references: 9504803
references: J Mol Biol. 1993 Dec 5;234(3):779-815
references: 8254673
references: Breast Cancer Res. 2005;7(3):86-95
references: 15987436
references: Stem Cells. 2004;22(7):1142-51
references: 15579635
references: J Natl Cancer Inst. 2006 Dec 20;98(24):1777-85
references: 17179479
references: Blood. 2004 Sep 15;104(6):1648-55
references: 15178579
references: Stem Cells. 2006 Apr;24(4):975-85
references: 16293577
references: J Natl Cancer Inst. 2008 May 7;100(9):672-9
references: 18445819
references: Cancer Biol Ther. 2009 Nov;8(22):2186-93
references: 19923910
references: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-8
references: 12629218
references: Biochem Pharmacol. 2001 Dec 15;62(12):1675-84
references: 11755121
references: Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2006 Jul;150(1):13-23
references: 16936898
references: Curr Opin Genet Dev. 2004 Feb;14(1):43-7
references: 15108804
references: Nucleic Acids Res. 2003 Jul 1;31(13):3497-500
references: 12824352
references: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3547-9
references: 12657737
references: J Mol Graph. 1990 Mar;8(1):52-6, 29
references: 2268628
references: Blood. 2004 Mar 15;103(6):2332-6
references: 14630803
references: Nature. 1992 Mar 5;356(6364):83-5
references: 1538787
references: Cell Stem Cell. 2007 Nov;1(5):555-67
references: 18371393
references: Nat Rev Cancer. 2003 Nov;3(11):832-44
references: 14668814
references: Nucleic Acids Res. 2005 Jan 1;33(Database issue):D266-8
references: 15608193
references: Neuro Endocrinol Lett. 2009;30 Suppl 1:60-6
references: 20027146
references: Hum Genomics. 2005 Jun;2(2):138-43
references: 16004729
references: Lung Cancer. 2009 Feb;63(2):227-34
references: 18619705
references: Arch Biochem Biophys. 1987 Nov 15;259(1):1-14
references: 3318697
references: Biochem Pharmacol. 2009 May 1;77(9):1466-79
references: 19426684
references: FEBS Lett. 2010 Aug 4;584(15):3392-7
references: 20600004
references: Proteins. 1993 Dec;17(4):355-62
references: 8108378
references: Mol Cancer. 2008 Nov 24;7:87
references: 19025616
references: Nat Rev Cancer. 2003 Dec;3(12):895-902
references: 14737120
references: Nucleic Acids Res. 1997 Sep 1;25(17):3389-402
references: 9254694
references: Blood. 2006 Mar 1;107(5):2162-9
references: 16269619
references: Anticancer Drugs. 2005 Aug;16(7):789-95
references: 16027529
references: J Mol Biol. 1990 Oct 5;215(3):403-10
references: 2231712
references: Cancer Lett. 2007 Jul 18;252(2):270-9
references: 17306925