Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Tumor Biology
Published in: Tumor Biology 1/2014

01-01-2014 | Research Article

Effects of ellipticine on ALDH1A1-expressing breast cancer stem cells—an in vitro and in silico study

Authors: Santhi Latha Pandrangi, Rajasekhar Chikati, Pradeep Singh Chauhan, Chitta Suresh Kumar, Anropa Banarji, Sunita Saxena

Published in: Tumor Biology | Issue 1/2014

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
2.
3.
Korkaya H, Paulson A, Charafe-Jauffret E, Ginestier C, Brown M, Dutcher J, et al. Regulation of mammary stem/progenitor cells by PTEN/Akt/beta-catenin signaling. PLoS Biol. 2009;7:e1000121.PubMedCentralPubMedCrossRef
4.
5.
Al-Hajj M, Becker MW, Wicha M, Weissman I, Clarke MF. Therapeutic implications of cancer stem cells. Curr Opin Genet Dev. 2004;14:43–7.PubMedCrossRef
6.
Dontu G, Al-Hajj M, Abdallah WM, Clarke MF, Wicha MS. Stem cells in normal breast development and breast cancer. Cell Prolif. 2003;36 Suppl 1:59–72.PubMedCrossRef
7.
Pardal R, Clarke MF, Morrison SJ. Applying the principles of stem-cell biology to cancer. Nat Rev Cancer. 2003;3:895–902.PubMedCrossRef
8.
Smalley M, Ashworth A. Stem cells and breast cancer: a field in transit. Nat Rev Cancer. 2003;3:832–44.PubMedCrossRef
9.
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003;100:3983–8.PubMedCentralPubMedCrossRef
10.
Croker AK, Goodale D, Chu J, Postenka C, Hedley BD, Hess DA, et al. High aldehyde dehydrogenase and expression of cancer stem cell markers selects for breast cancer cells with enhanced malignant and metastatic ability. J Cell Mol Med. 2009;13:2236–52.PubMedCrossRef
11.
Ucar D, Cogle CR, Zucali JR, Ostmark B, Scott EW, Zori R, et al. Aldehyde dehydrogenase activity as a functional marker for lung cancer. Chem Biol Interact. 2009;178:48–55.PubMedCentralPubMedCrossRef
12.
Corti S, Locatelli F, Papadimitriou D, Donadoni C, Salani S, Del Bo R, et al. Identification of a primitive brain-derived neural stem cell population based on aldehyde dehydrogenase activity. Stem Cells. 2006;24:975–85.PubMedCrossRef
13.
Vasiliou V, Nebert DW. Analysis and update of the human aldehyde dehydrogenase (ALDH) gene family. Hum Genomics. 2005;2:138–43.PubMedCentralPubMed
14.
Armstrong L, Stojkovic M, Dimmick I, Ahmad S, Stojkovic P, Hole N, et al. Phenotypic characterization of murine primitive hematopoietic progenitor cells isolated on basis of aldehyde dehydrogenase activity. Stem Cells. 2004;22:1142–51.PubMedCrossRef
15.
Hess DA, Meyerrose TE, Wirthlin L, Craft TP, Herrbrich PE, Creer MH, et al. Functional characterization of highly purified human hematopoietic repopulating cells isolated according to aldehyde dehydrogenase activity. Blood. 2004;104:1648–55.PubMedCrossRef
16.
Hess DA, Wirthlin L, Craft TP, Herrbrich PE, Hohm SA, Lahey R, et al. Selection based on CD133 and high aldehyde dehydrogenase activity isolates long-term reconstituting human hematopoietic stem cells. Blood. 2006;107:2162–9.PubMedCrossRef
17.
18.
Goodwin S, Smith AF. Alkaloids of Ochrosia elliptica Labill. J Am Chem Soc. 1959;81:1903–8.CrossRef
19.
Stiborova M. The anticancer drug ellipticine forms covalent DNA adducts, mediated by human cytochromes P450, through metabolism to 13-hydroxyellipticine and ellipticine N2-oxide. Cancer Res. 2004;64:8374–80.PubMedCrossRef
20.
Stiborova M, Rupertova M, Schmeiser HH, Frei E. Molecular mechanisms of antineoplastic action of an anticancer drug ellipticine. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2006;150:13–23.PubMedCrossRef
21.
Kuo PL, Hsu YL, Kuo YC, Chang CH, Lin CC. The anti-proliferative inhibition of ellipticine in human breast mda-mb-231 cancer cells is through cell cycle arrest and apoptosis induction. Anticancer Drugs. 2005;16:789–95.PubMedCrossRef
22.
Poljakova J, Eckschlager T, Hrabeta J, Hrebackova J, Smutny S, Frei E, et al. The mechanism of cytotoxicity and DNA adduct formation by the anticancer drug ellipticine in human neuroblastoma cells. Biochem Pharmacol. 2009;77:1466–79.PubMedCrossRef
23.
Martinkova E, Dontenwill M, Frei E, Stiborova M. Cytotoxicity of and DNA adduct formation by ellipticine in human U87MG glioblastoma cancer cells. Neuro Endocrinol Lett. 2009;30 Suppl 1:60–6.PubMed
24.
Auclair C. Multimodal action of antitumor agents on DNA: the ellipticine series. Arch Biochem Biophys. 1987;259:1–14.PubMedCrossRef
25.
Huang C, Zhang XM, Tavaluc RT, Hart LS, Dicker DT, Wang W, et al. The combination of 5-fluorouracil plus p53 pathway restoration is associated with depletion of p53-deficient or mutant p53-expressing putative colon cancer stem cells. Cancer Biol Ther. 2009;8:2186–93.PubMedCrossRef
26.
Dontu G, Abdallah WM, Foley JM, Jackson KW, Clarke MF, Kawamura MJ, et al. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev. 2003;17:1253–70.PubMedCrossRef
27.
Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007;1:555–67.PubMedCentralPubMedCrossRef
28.
Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool. J Mol Biol. 1990;215:403–10.PubMed
29.
Altschul SF, Madden TL, Schäffer AA, Zhang J, Zhang Z, Miller W, et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 1997;25:3389–402.PubMedCentralPubMedCrossRef
30.
31.
Sali A, Blundell TL. Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol. 1993;234:779–815.PubMedCrossRef
32.
Guex N, Peitsch MC. SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis. 1997;18:2714–23.PubMedCrossRef
33.
Laskowski RA, MacArthur MW, Moss DS, Thornton JM. PROCHECK: a program to check the stereochemical quality of protein structures. J Appl Crystallogr. 1993;26:283–91.CrossRef
34.
35.
Sippl MJ. Recognition of errors in three-dimensional structures of proteins. Proteins. 1993;17:355–62.PubMedCrossRef
36.
Lüthy R, Bowie JU, Eisenberg D. Assessment of protein models with three-dimensional profiles. Nature. 1992;356:83–5.CrossRef
37.
Bowie JU, Lüthy R, Eisenberg D. A method to identify protein sequences that fold into a known three-dimensional structure. Science. 1991;253:164–70.PubMedCrossRef
38.
Laskowski RA, Chistyakov VV, Thornton JM. Pdbsum more: new summaries and analyses of the known 3D structures of proteins and nucleic acids. Nucleic Acids Res. 2005;33:D266–268.PubMedCentralPubMedCrossRef
39.
Lindal E, Hess B. Gromacs 3.0: a package for molecular simulation and trajectory analysis. J Mol Model. 2001;7:306–17.
40.
Berendsen H. Interaction models for water in relation to protein hydration. In: Pullman B, editor. Intermolecular forces. Dordrecht: Reidel; 1981. p. 331–42.
41.
42.
Fosse P, Rene B, Charra M, Paoletti C, Saucier JM. Stimulation of topoisomerase II-mediated DNA cleavage by ellipticine derivatives: structure–activity relationship. Mol Pharmacol. 1992;42:590–5.PubMed
43.
Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst. 2008;100:672–9.PubMedCrossRef
44.
Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C, et al. let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell. 2007;131:1109–23.PubMedCrossRef
45.
Charafe-Jauffret E, Monville F, Ginestier C, Dontu G, Birnbaum D, Wicha MS. Cancer stem cells in breast: current opinion and future challenges. Pathobiology. 2008;75:75–84.PubMedCentralPubMedCrossRef
46.
Ohashi M, Sugikawa E, Nakanishi N. Inhibition of p53 protein phosphorylation by 9-hydroxyellipticine: a possible anticancer mechanism. Jpn J Cancer Res. 1995;86:819–27.PubMedCrossRef
47.
Stiborova M, Bieler CA, Wiessler M, Frei E. The anticancer agent ellipticine on activation by cytochrome P450 forms covalent DNA adducts. Biochem Pharmacol. 2001;62:1675–84.PubMedCrossRef
48.
Poljakova J, Frei E, Gomez JE, Aimova D, Eckschlager T, Hrabeta J, et al. DNA adduct formation by the anticancer drug ellipticine in human leukemia HL-60 and CCRF-CEM cells. Cancer Lett. 2007;252:270–9.PubMedCrossRef
49.
Tian E, Landowski TH, Stephens OW, Yaccoby S, Barlogie B, Shaughnessy Jr JD. Ellipticine derivative NSC 338258 represents a potential new antineoplastic agent for the treatment of multiple myeloma. Mol Cancer Ther. 2008;7:500–9.PubMedCrossRef
50.
Fang K, Chen SP, Lin CW, Cheng WC, Huang HT. Ellipticine-induced apoptosis depends on Akt translocation and signaling in lung epithelial cancer cells. Lung Cancer. 2009;63:227–34.PubMedCrossRef
51.
Juret P, Couette JE, Delozier T, Le Talaer JY. [Hydroxy-9-methyl-2-ellipticinium (NSC 264-137) for osseous metastases from breast cancer. A 4 year experience (author’s transl)]. Bull Cancer. 1981;68:224–31.PubMed
52.
Peng Y, Li C, Chen L, Sebti S, Chen J. Rescue of mutant p53 transcription function by ellipticine. Oncogene. 2003;22:4478–87.PubMedCrossRef
53.
Wang X, Wu X, Wang C, Zhang W, Ouyang Y, Yu Y, He Z. Transcriptional suppression of breast cancer resistance protein (BCRP) by wild-type p53 through the NF-kappaB pathway in MCF-7 cells. FEBS Lett. 2010;584:3392–7.
54.
Godar S, Ince TA, Bell GW, Feldser D, Donaher JL, Bergh J, et al. Growth-inhibitory and tumor-suppressive functions of p53 depend on its repression of CD44 expression. Cell. 2008;134:62–73.PubMedCentralPubMedCrossRef
55.
Phillips TM, McBride WH, Pajonk F. The response of CD24(−/low)/CD44+ breast cancer-initiating cells to radiation. J Natl Cancer Inst. 2006;98:1777–85.PubMedCrossRef
56.
Moreb JS, Baker HV, Chang L-J, Amaya M, Lopez MC, Ostmark B, et al. ALDH isozymes downregulation affects cell growth, cell motility and gene expression in lung cancer cells. Mol Cancer. 2008;7:87–87.PubMedCentralPubMedCrossRef
Metadata
Title
Effects of ellipticine on ALDH1A1-expressing breast cancer stem cells—an in vitro and in silico study
Authors
Santhi Latha Pandrangi
Rajasekhar Chikati
Pradeep Singh Chauhan
Chitta Suresh Kumar
Anropa Banarji
Sunita Saxena
Publication date
01-01-2014
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 1/2014
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-013-1099-y

Other articles of this Issue 1/2014

Tumor Biology 1/2014 Go to the issue

Research Article

The rs1050450 C > T polymorphism of GPX1 is associated with the risk of bladder but not prostate cancer: evidence from a meta-analysis

Research Article

Effect of GSTM1 null genotype on risk of childhood acute leukemia: a meta-analysis

Research Article

The association of SIPA1 gene polymorphisms with breast cancer risk: evidence from published studies

Research Article

GSTT1 null genotype contributes to hepatocellular carcinoma risk: a meta-analysis

Research Article

RETRACTED ARTICLE: Association between glutathione S-transferase M1 null genotype and risk of gallbladder cancer: a meta-analysis

Research Article

IGF-1R and Bmi-1 expressions in lung adenocarcinoma and their clinicopathologic and prognostic significance
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits