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
Investigational New Drugs
Published in: Investigational New Drugs 6/2014

01-12-2014 | PRECLINICAL STUDIES

Ellipticine derivative induces potent cytostatic effect in acute myeloid leukaemia cells

Authors: E. G. Russell, E. C. O’Sullivan, C. M. Miller, J. Stanicka, F. O. McCarthy, T. G. Cotter

Published in: Investigational New Drugs | Issue 6/2014

Login to get access

Summary

A panel of novel ellipticine isomers were designed and synthesised with the aim of evaluating their anti-cancer effects on selected leukaemia cell lines. A preliminary NCI 60-cell screen demonstrated that these compounds display promising anti-tumour activity across a number of different cell types. We have consequently examined the effect of these derivatives in detail on the Acute Myeloid Leukaemia (AML) cell line, MV4-11. Cell cycle analyses revealed that the compounds had a range of distinctive cell cycle effects. 7-Hydroxyisoellipticine showed the most promise with respect to cytostatic activity. We demonstrated that this compound inhibited proliferation of leukaemia cells by preventing cells from progressing from G2 phase into mitosis over a period of 24 h at a concentration of 5 μM. Our research suggests that this is mediated by an induction of reactive oxygen species (ROS), which in turn activates the DNA damage response pathway. As a result of the activation of p53, cyclin B1 is inhibited. The induction of this pathway leads to apoptosis which is seen at 48 h using the same dose of 7-hydroxyisoellipticine. This study provides for the first time detailed cellular information on the potential use of isoellipticines as chemotherapeutic agents.
Literature
1.
Goodwin S, Smith AF, Horning EC (1959) Alkaloids of ochrosia elliptica labill. J Am Chem Soc 81:1903–1908CrossRef
2.
Dalton LK, Demerac S, Elmes BC, Loder JW, Swan JM, Teitei T (1967) Synthesis of the tumor-inhibitory alkaloids, ellipticine, 9-methoxyellipticine, and related pyrido-[4,3-b]carbazoles. Aust J Chem 20:2715–2727CrossRef
3.
Sbai M, Lyazidi SA, Lerner DA, Castillo DB, Martin MA (1996) Stoichiometry and association constants of the inclusion complexes of ellipticine with modified P-cyclodextrin. Analyst 121:1561–1564CrossRef
4.
Miller CM, O’Sullivan EC, Devine KJ, McCarthy FO (2012) Synthesis and biological evaluation of novel isoellipticine derivatives and salts. Org Biomol Chem 10(39):7912–7921CrossRefPubMed
5.
6.
Handin RI, Lux SE, Stosse TP, Babior BM (2003) Blood: principles and practice of hematology, 2nd edition, Lippincott. Williams and Wilkins, Philidelphia, pp 483–530
7.
Lowenberg B (1996) Treatment of the elderly patient with acute myeloid leukaemia. Baillieres Clin Haematol 9(1):147–159CrossRefPubMed
8.
O’ Sullivan EC, Miller CM, Deane FM, McCarthy FO (2012) Emerging targets in the bioactivity of ellipticines and derivatives. Studies in natural products chemistry, chapter 6. Elsevier Science Publishers, Amsterdam, pp 189–226
9.
Deane FM, O’Sullivan EC, Maguire AR, Gilbert J, Sakoff JA, McCluskey A et al (2013) Synthesis and evaluation of novel ellipticines as potential anti-cancer agents. Org Biomol Chem 11(8):1334–1344CrossRefPubMed
10.
Lerman LS (1961) Structural considerations in the interaction of DNA and acridines. J Mol Biol 3:18–30CrossRefPubMed
11.
Ross WE, Glaubiger D, Kohn KW (1978) Protein-associated DNA breaks in cells treated with Adriamycin or ellipticine. Biochim Biophys Acta 519(1):23–30CrossRefPubMed
12.
Auclair C, Paoletti C (1981) Bioactivation of the antitumor drugs 9-hydroellipticine and derivatives by a peroxidase-hydrogen peroxide system. J Med Chem 24(3):289–295CrossRefPubMed
13.
Kuo PL, Hsu YL, Kuo YC, Chang CH, Lin CC (2005) The anti-proliferative inhibition of ellipticine in human breast mda-mb-231 cancer cells is through cell cycle arrest and apoptosis induction. Anticancer Drugs 7:789–795CrossRef
14.
Hagg M, Berndtsson M, Mandic A, Zhou R, Shoshan MC, Linder S (2004) Induction of endoplasmic reticulum stress by ellipticine plant alkaloids. Mol Cancer Ther 3:489–497PubMed
15.
Jin X, Gossett DR, Wang S, Yang D, Cao Y, Chen J et al (2004) Inhibition of AKT survival pathway by a small molecule inhibitor in human endometrial cancer cells. Br J Cancer 91(10):1808–1812PubMedCentralCrossRefPubMed
16.
Vendome J, Letard S, Martin F, Svinarchuk F, Dubreuil P, Auclair C et al (2005) Molecular modelling of wild-type and D816V c-kit inhibition based on ATP-competitive binding of ellipticine derivatives to tyrosine kinases. J Med Chem 48:6194–6201CrossRefPubMed
17.
Prudent R, Moucadel V, Nguyen CH, Barette C, Schmidt F, Florent JC, Lafanechere L, Sautel CF, Duchemin-Pelletier E, Spreux E, Filhol O, Reiser JB, Cochet C (2010) Antitumor activity of pyridocarbazole and benzopyridoindole derivatives that inhibit protein kinase CK2. Cancer Res 70(23):9865–9874CrossRefPubMed
18.
Peng Y, Li C, Chen L, Sebti S, Chen J (2003) Rescue of Mutant p53 transcription function by ellipticine. Oncogene 22(29):4478–4487CrossRefPubMed
19.
20.
Chung YW, Jeong DW, Won JY, Choi EJ, Choi YH, Kim IJ (2002) H2O2-induced AP-1 activation and its effect on p21WAF1/CIP1-mediated G2/M arrest in a p53-deficient human lung cancer cell. Biochem Biophys Res Commun 293:1248–1253CrossRefPubMed
21.
22.
Simbulan-Rosenthal CM, Rosenthal DS, Iyer S, Boulares H, Smulson ME (1999) Involvement of PARP and poly(ADP-ribosyl)ation in the early stages of apoptosis and DNA replication. Mol Cell Biochem 193:137–148CrossRefPubMed
23.
Gribble GW, Saulnier MG, Obaza-Nutaitis JA, Ketcha DM (1992) J Org Chem 57:5891–5899CrossRef
24.
Kim JY, Lee SG, Chung JY, Kim YJ, Park JE, Koh H et al (2011) Ellipticine induces apoptosis in human endometrial cancer cells: the potential involvement of reactive oxygen species and mitogen-activated protein kinases. Toxicology 289(2–3):91–102CrossRefPubMed
25.
26.
Bennett MR (2001) Reactive oxygen species and death: oxidative DNA damage in atherosclerosis. Circ Res 88:648–650CrossRefPubMed
27.
Lakin ND, Jackson SP (1999) Regulation of p53 in response to DNA damage. Oncogene 18(53):7644–7655CrossRefPubMed
28.
Girardi C, James P, Zanin S, Pinna LA, Ruzzene M (2014) Differential phosphorylation of Akt1 and Akt2 by protein kinase CK2 may account for isoform specific functions. Biochim Biophys Acta 1843(9):1865–1874CrossRefPubMed
29.
Meggio F, Pinna LA (2003) One-thousand-and-one substrates of protein kinase CK2? FASEB J 17(3):349–368CrossRefPubMed
30.
Lee SR, Park JH, Park EK, Chung CH, Kang SS, Bang OS (2005) Akt-induced promotion of cell-cycle progression at G2/M phase involves upregulation of NF-Y binding activity in PC12 cells. J Cell Physiol 205(2):270–277CrossRefPubMed
31.
Gutierrez GJ, Tsuji T, Cross JV, Davis RJ, Templeton DJ, Jiang W, Ronai ZA (2010) JNK-mediated phosphorylation of Cdc25C regulates cell cycle entry and G2/M DNA damage checkpoint. J Biol Chem 285:14217–14228PubMedCentralCrossRefPubMed
32.
Park EJ, Kiselev E, Conda-Sheridan M, Cushman M, Pezzuto JM (2012) Induction of apoptosis by 3-amino-6-(3-aminopropyl)-5,6-dihydro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline via modulation of MAPKs (p38 and c-Jun N-terminal kinase) and c-Myc in HL-60 human leukemia cells. J Nat Prod 75(3):378–384PubMedCentralCrossRefPubMed
33.
34.
Sureau F, Moreau F, Millot JM, Manfait M, Allard B, Aubard J et al (1993) Microspectrofluorometry of the protonation state of ellipticine, an antitumor alkaloid, in single cells. Biophys J 65(5):1767–1774PubMedCentralCrossRefPubMed
35.
Schumacker PT (2006) Reactive oxygen species in cancer cells: live by the sword, die by the sword. Cancer Cell 10(3):175–176CrossRefPubMed
36.
Thorn T, GniadeckiR PAB, Vicanova J, Wulf HC (2001) Differences in activation of G2/M checkpoint in keratinocytes after genotoxic stress induced by hydrogen peroxide and ultraviolet radiation. Free Radic Res 35:405–416CrossRefPubMed
37.
Zhang Z, Huang C, Li J, Leonard SS, Lanciotti R, Butterworth L et al (2001) Vanadate-induced cell growth regulation and the role of reactive oxygen species. Arch Biochem Biophys 392:311–320CrossRefPubMed
38.
Zhang Z, Leonard SS, Huang C, Vallyathan V, Castranova V, Shi X (2003) Role of reactive oxygen species and MAPKs in vanadate-induced G2/M phase arrest. Free Radic Biol Med 34:1333–1342CrossRefPubMed
39.
Bijur GN, Briggs B, Hitchcock CL, Williams MV (1999) Ascorbic acid-dehydroascorbate induces cell cycle arrest at G2/M DNA damage checkpoint during oxidative stress. Environ Mol Mutagen 33:144–152CrossRefPubMed
40.
Fernandez-Capetillo O, Lee A, Nussenzweig M, Nussenzweig A (2004) H2AX: the histone guardian of the genome. DNA Repair 3:959–967CrossRefPubMed
41.
42.
Sugikawa E, Hosoi T, Yazaki N, Gamanuma M, Nakanishi N, Ohashi M (1999) Mutant p53 mediated induction of cell cycle arrest and apoptosis at G1 phase by 9-hydroxyellipticine. Anticancer Res 19(4B):3099–3108PubMed
43.
Ohashi M, Sugikawa E, Nakanishi N (1995) Inhibition of p53 protein phosphorylation by 9-hydroxyellipticine: a possible anticancer mechanism. Jpn J Cancer Res 86(9):819–827CrossRefPubMed
44.
Metadata
Title
Ellipticine derivative induces potent cytostatic effect in acute myeloid leukaemia cells
Authors
E. G. Russell
E. C. O’Sullivan
C. M. Miller
J. Stanicka
F. O. McCarthy
T. G. Cotter
Publication date
01-12-2014
Publisher
Springer US
Published in
Investigational New Drugs / Issue 6/2014
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-014-0140-3

Other articles of this Issue 6/2014

Investigational New Drugs 6/2014 Go to the issue

PRECLINICAL STUDIES

Irinophore C™, a lipid nanoparticle formulation of irinotecan, abrogates the gastrointestinal effects of irinotecan in a rat model of clinical toxicities

PHASE I STUDIES

A phase I trial of pantoprazole in combination with doxorubicin in patients with advanced solid tumors: evaluation of pharmacokinetics of both drugs and tissue penetration of doxorubicin

PHASE I STUDIES

Phase I dose-escalation study of SGN-75 in patients with CD70-positive relapsed/refractory non-Hodgkin lymphoma or metastatic renal cell carcinoma

PRECLINICAL STUDIES

CG100649, a novel COX-2 inhibitor, inhibits colorectal adenoma and carcinoma growth in mouse models

PRECLINICAL STUDIES

Ibrutinib (ImbruvicaTM) potently inhibits ErbB receptor phosphorylation and cell viability of ErbB2-positive breast cancer cells

PHASE I STUDIES

A phase I, dose-escalation trial of continuous- and pulsed-dose afatinib combined with pemetrexed in patients with advanced solid tumors
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