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 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Cancer Cell International
Published in: Cancer Cell International 1/2015

Open Access 01-12-2015 | Primary research

Induction of atypical cell death in thyroid carcinoma cells by the indirubin derivative 7-bromoindirubin-3′-oxime (7BIO)

Authors: Martina Broecker-Preuss, Nina Becher-Boveleth, Susanne Gall, Katrin Rehmann, Susann Schenke, Klaus Mann

Published in: Cancer Cell International | Issue 1/2015

Login to get access

Abstract

Background

The indirubin derivative 7-bromoindirubin-3′-oxime (7BIO) has already shown anticancer properties by causing cell death in some tumour cell lines and may be a new therapeutic option for treatment-resistant tumour cells. Since dedifferentiated and anaplastic thyroid carcinomas do not take up radioiodine and are insensitive to chemotherapeutic treatment and external radiation, direct cell death induction in these tumour cells may be a promising approach. We thus investigated the effect of 7BIO on thyroid carcinoma cell lines of different histological origins and characterized the type of cell death induction by 7BIO.

Methods

Cell viability was measured with MTT assay. Cell death was analysed by caspase 3/7 activity, lactate dehydrogenase liberation, caspase cleavage products, DNA fragmentation, cell cycle phase distribution and LC3B analysis.

Results

After 7BIO treatment, cell viability was reduced in all 14 thyroid carcinoma cell lines investigated. Treated cells showed DNA fragmentation, cell cycle arrest and lactate dehydrogenase liberation but no LC3B cleavage. Caspase activation following 7BIO treatment was found in five of six cell lines investigated. Interestingly, inhibition of caspases had no effect on viability of the cells after 7BIO incubation.

Conclusions

Our results indicate that 7BIO efficiently killed dedifferentiated thyroid carcinoma cells. It induced a non-classical kind of cell death that was caspase-independent and includes DNA fragmentation. 7BIO and related indirubin components thus may have value as a new therapeutic option for dedifferentiated thyroid cancer irrespective of the exact target molecules and the kind of cell death they induce.
Literature
1.
Xiao Z, Hao Y, Liu B, Qian L. Indirubin and meisoindigo in the treatment of chronic myelogenous leukemia in China. Leuk Lymphoma. 2002;43:1763–8.CrossRefPubMed
2.
Cooksey CJ. Tyrian purple: 6,6′-dibromoindigo and related compounds. Molecules. 2001;6:736–69.CrossRef
3.
Ribas J, Bettayeb K, Ferandin Y, Knockaert M, Garrofé-Ochoa X, Totzke F, Schächtele C, Mester J, Polychronopoulis P, Magiatis P, Skaltsounis A-L, Boix J, Meijer L. 7-Bromoindirubin-3′-oxime induces caspase-independent cell death. Oncogene. 2006;25:6304–18.CrossRefPubMed
4.
Ribas J, Yuste VJ, Garrofé-Ochoa X, Meijer L, Esquerda JE, Boix J. 7-Bromoindirubin-3′-oxime uncovers a serine protease-mediated paradigm of necrotic cell death. Biochem Pharmacol. 2008;76:39–52.CrossRefPubMed
5.
Nicolaou KA, Liapis V, Evdokiou A, Constantinou C, Magiatis P, Skaltsounis AL, Koumas L, Costeas PA, Constantinou AI. Induction of discrete apoptotic pathways by bromo-substituted indirubin derivatives in invasive breast cancer cell. Biochem Biophys Res Commun. 2012;425:76–82.CrossRefPubMed
6.
Hoessel R, Leclerc S, Endicott J, Noble M, Lawrie A, Tunnah P, Leost M, Damiens E, Marie D, Marko D, Niederberger E, Tang W, Eisenbrand G, Meijer L. Indirubin, the active constituent of a chinese antileukaemia medicine, inhibits cyclin-dependent kinases. Nat Cell Biol. 1999;1:60–7.CrossRefPubMed
7.
Liu L, Nam S, Tian Y, Yang F, Wu J, Wang Y, Scuto A, Polychronopoulos P, Magiatis P, Skaltsounis L, Jove R. 6-Bromoindirubin-3′-oxime inhibits JAK/STAT3 signaling and induces apoptosis of human melanoma cells. Cancer Res. 2011;71:3972–8.PubMedCentralCrossRefPubMed
8.
Liu L, Gaboriaud N, Vougogianopoulou K, Tian Y, Wu J, Wen W, Skaltsounis L, Jove R. MLS-2384, a new 6-bromoindirubin derivative with dual JAK/Src kinase inhibitory activity, suppresses growth of diverse cancer cells. Cancer Biol Ther. 2014;15:178–84.PubMedCentralCrossRefPubMed
9.
Nam S, Wen W, Schroeder A, Herrmann A, Yu H, Cheng X, Merz K-H, Eisenbrand G, Li H, Yuan Y-C, Jove R. Dual inhibition of Janus and Src family kinases by novel indirubin derivative blocks constitutively-activated Stat3 signaling associated with apoptosis of human pancreatic cancer cells. Mol Oncol. 2013;7:369–78.PubMedCentralCrossRefPubMed
10.
Liu L, Kritsanida M, Magiatis P, Gaboriaud N, Wang Y, Wu J, Buettner R, Yang F, Nam S, Skaltsounis L, Jove R. A novel 7-bromoindirubin with potent anticancer activity suppresses survival of human melanoma cells associated with inhibition of STAT3 and Akt signalling. Cancer Biol Ther. 2012;13:1255–61.PubMedCentralCrossRefPubMed
11.
Nam S, Scuto A, Yang F, Chen WY, Park S, Yoo H-S, Konig H, Bhatia R, Cheng X, Merz K-H, Eisenbrand G, Jove R. Indirubin derivatives induce apoptosis of chrinoc myelogenous leujemia cells involving inhibition of Stat5 signaling. Mol Oncol. 2012;6:276–83.PubMedCentralCrossRefPubMed
12.
13.
14.
Long JS, Ryan KM. New frontiers in promoting tumour cell death: targeting apoptosis, necroptosis and autophagy. Oncogene. 2012;31:5045–60.CrossRefPubMed
15.
Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MV, Dawson TM, Dawson VL, El-Deiry WS, Fulda S, Gottlieb E, Green DR, Hengartner MO, Kepp O, Knight RA, Kumar S, Lipton SA, Lu X, Madeo F, Malorni W, Mehlen P, Nunez G, Peter ME, Piacentini M, Rubinsztein DC, Shi Y, Simon H-U, Vandenabeele P, White E, Yuan J, Zhivitivsky B, Melino G, Kroemer G. Molecular definitions of cell death subroutines: recommendations of the nomenclature committee on cell death 2012. Cell Death Differ. 2012;19:107–20.PubMedCentralCrossRefPubMed
16.
Budihardjo I, Oliver H, Lutter M, Luo X, Wang X. Biochemical pathways of caspase activation during apoptosis. Annu Rev Cell Dev Biol. 1999;15:269–90.CrossRefPubMed
17.
Kerr JFR, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972;26:239–57.PubMedCentralCrossRefPubMed
18.
Ferri KF, Kroemer G. Organelle-specific initiation of cell death pathways. Nat Cell Biol. 2001;3:E255–63.CrossRefPubMed
19.
Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G. Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol. 2010;11:700–14.CrossRefPubMed
20.
Artal-Sanaz M, Samara C, Syntichaki P, Tavernarankis N. Lysosomal biogenesis and function is critical for necrotic cell death in Caenorhabditis elegans. J Cell Biol. 2006;173:231–9.CrossRef
21.
Choi AMK, Ryter SW, Levine B. Autophagy in human health and disease. New Engl J Med. 2013;368:651–62.CrossRefPubMed
22.
Levine B, Klionsky DJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell. 2004;6:463–77.CrossRefPubMed
23.
Kapiteijn E, Schneider TC, Morreau H, Gelderblom H, Nortier JWR, Smit JWA. New treatment modalities in advanced thyroid cancer. Ann Oncol. 2012;23:10–8.CrossRefPubMed
24.
Kondo T, Ezzat S, Asa SL. Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer. 2006;6:292–306.CrossRefPubMed
25.
26.
Baudin E, Schlumberger M. New therapeutic approaches for metastatic thyroid carcinoma. Lancet Oncol. 2007;8:148–56.CrossRefPubMed
27.
Kebebew E, Greenspan FS, Clark OH, Woeber KA, McMillan A. Anaplastic thyroid carcinoma. Treatment, outcome and prognostic factors. Cancer. 2005;103:1330–5.CrossRefPubMed
28.
Schlumberger M, Sherman SI. Approach to the patient with advanced differentiated thyroid cancer. Eur J Endocrinol. 2012;166:5–11.CrossRefPubMed
29.
Sherman SI. Cytotoxic chemotherapy for differentiated thyroid carcinoma. Clin Oncol (R Coll Radiol). 2010;22:464–8.CrossRefPubMed
30.
Miccoli P, Materazzi G, Antonelli A, Panicucci E, Frustaci G, Berti P. New trends in the treatment of undifferentiated carcinomas of the thyroid. Langenbecks Arch Surg. 2007;392:397–404.CrossRefPubMed
31.
Mark J, Ekedahl C, Dahlenfors R, Westermark B. Cytogenetical observations in five human anaplastic thyroid carcinomas. Hereditas. 1987;107:163–74.CrossRefPubMed
32.
Carlson J, Nilsson K, Westermark B, Ponten J, Sundstöm C, Larsson E, Bergh J, Pahlman S, Busch C, Collins VP. Formation and growth of multicellular spheroids of human origin. Int J Cancer. 1983;31:523–33.CrossRef
33.
Heldin N-E, Gustavson B, Claesson-Welsh L, Hammacher A, Mark J, Heldin C-H, Westermark B. Aberrant expression of receptors for PDGF in an anaplastic thyroid carcinoma cell line. Proc Natl Acad Sci USA. 1988;85:9302–6.PubMedCentralCrossRefPubMed
34.
Heldin NE, Cvejic D, Smeds S, Westermark B. Coexpression of functionally active receptors for thyrotropin and platelet-derived growth factor in human thyroid carcinoma cells. Endocrinology. 1991;129:2187–93.CrossRefPubMed
35.
Ito T, Seyama T, Mizuno T, Tsuyama N, Hayashi T, Hayashi Y, Dohi K, Nakamura N, Akiyama M. Unique association of p53 mutations with undifferentiated but not with differentiated carcinomas of the thyroid gland. Cancer Res. 1992;52:1369–71.PubMed
36.
Ito T, Seyama T, Hayashi Y, Hayashi T, Dohi K, Mizuno T, Iwamoto K, Tsuyama N, Nakamura N, Akiyama M. Establishment of 2 human thyroid-carcinoma cell-lines (8305c, 8505c) bearing p53 gene-mutations. Int J Oncol. 1994;4:583–6.PubMed
37.
Pályi I, Péter I, Daubner D, Vincze B, Lórincz I. Establishment, characterization and drug sensitivity of a new anaplastic thyroid carcinoma cell line (BHT-101). Virchows Archiv B Cell Pathol. 1993;63:263–9.CrossRef
38.
Fabien N, Fusco A, Santoro M, Barbier Y, Dubois PM, Paulin C. Description of a human papillary thyroid carcinoma cell line. Morphologic study and expression of tumoral markers. Cancer. 1994;73:2206–12.CrossRefPubMed
39.
Tanaka J, Ogura T, Sato H, Hatano M. Establishment and biological characterization of an in vitro human cytomegalovirus latency model. Virology. 1987;161:62–72.CrossRefPubMed
40.
Schönberger J, Bauer J, Spruß T, Weber G, Chahoud I, Eilles C, Grimm D. Establishment and characterization of the follicular thyroid carcinoma cell line ML-1. J Mol Med. 2000;78:102–10.CrossRefPubMed
41.
Geldorf AA, Versteegh LRT, van Mourik JC, Rooimans MA, Arwert F, Hermsen MA, Schadee-Eestermans IL, van Dongen GA, van der Valk P, van der Clement EHP, Lips P, Teule GJ. Clonally related but phenotypically divergent human cancer cell lines derived from a single follicular thyroid cancer recurrence (TT2609). Thyroid. 2001;11:909–17.CrossRef
42.
Goretzki PE, Frilling A, Simon D, Rastegar M, Ohmann C. Growth regulation of human thyrocytes by thyrotropin, cyclic adenosine monophosphate, epidermal growth factor and insulin-like growth factor. Front Horm Res Basel Karger. 1989;18:56–80.CrossRef
43.
Stepczynska A, Lauber K, Engels IH, Janssen O, Kabelitz D, Wesselborg S, Schulze-Osthoff K. Staurosporine and conventional anticancer drugs induce overlapping, yet distinct pathways of apoptosis and caspase activation. Oncogene. 2001;20:1193–202.CrossRefPubMed
44.
Su JC, Tseng PH, Hsu CY, Tai WT, Huang JW, Ko CH, Lin MW, Liu CY, Chen KF, Shiau CW. RFX-dependent activation of SHP-1 induces autophagy by a novel obatoclax derivative in hepatocellular carcinoma cells. Oncotarget. 2014;5:4909–19.PubMedCentralCrossRefPubMed
45.
Ferandin Y, Bettayeb K, Kritsanida M, Lozach O, Polychronopoulos P, Magiatis P, Skaltsounis AL, Meijer L. 3′-Substituted 7-halogenoindirubins, a new class of cell death inducing agents. J Med Chem. 2006;49:4638–49.CrossRefPubMed
46.
47.
Okuno S, Shimizu S, Ito T, Nomura M, Hamada E, Tsujimoto Y, Matsuda H. Bcl-2 prevents caspase-independent cell death. J Biol Chem. 1998;273:34272–7.CrossRefPubMed
48.
Denmeade SR, Lin XS, Tombal B, Isaacs JT. Inhibition of caspase activity does not prevent the signalling phase of apoptosis in prostate cancer cells. Prostate. 1999;39:269–79.CrossRefPubMed
49.
50.
Hagen E, Blomgren K, Bénit P, Kroemer G, Modjtahedi N. Life with or without AIF. Trends Biochem Sci. 2010;35:278–87.CrossRef
51.
Egger L, Schneider J, Rheme C, Tapernoux M, Häcki J, Borner C. Serine proteases mediate apoptosis-like cell death and phagocytosis under caspase-inhibiting conditions. Cell Death Differ. 2003;10:1188–203.CrossRefPubMed
52.
Deiss LP, Galinka H, Berissi H, Cohen O, Kimchi A. Cathepsin D protease mediates programmed cell death induced by interferon-gamma, Fas/APO-1 and TNF-alpha. EMBO J. 1996;15:3861–70.PubMedCentralPubMed
53.
Guicciardi ME, Deussing J, Miyoshi H, Bronk SF, Svingen PA, Peters C, Kaufmann SH, Gores GJ. Cathepsin B contributes to TNF-alpha—mediated hepatocyte apoptosis by promoting mitochondrial release of cytochrome c. J Clin Invest. 2000;106:1127–37.PubMedCentralCrossRefPubMed
54.
Johnson DE. Noncaspase proteases in apoptosis. Leukemia. 2000;14:1696–703.
55.
Nakagawa T, Yuan J. Cross-talk between two cysteine protease families. Activation of caspase-12 by calpain in apoptosis. J Cell Biol. 2000;150:887–94.PubMedCentralCrossRefPubMed
56.
Hughes FM, Evans-Storms RB, Cidlowski JA. Evidence that non-caspase proteases are required for chromatin degradation during apoptosis. Cell Death Differ. 1998;5:1017–27.CrossRefPubMed
57.
Kitazumi I, Tsukahara M. Regulation of DNA fragmentation: the role of caspases and phosphorylation. FEBS J. 2010;278:427–41.CrossRefPubMed
58.
59.
Samara C, Syntichaki P, Tavernarakis N. Autophagy is required for necrotic cell death in Caenorhabditis elegans. Cell Death Differ. 2008;15:105–12.CrossRefPubMed
60.
Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D, Pouyssegur J, Mazure NM. Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3 L via their BH3 domains. Mol Cell Biol. 2009;29:2570–81.PubMedCentralCrossRefPubMed
61.
Damiens E, Baratte B, Marie D, Eisenbrand G, Meijer L. Anti-mitotic properties of indirubin-3′-monoxime, a CDK/GSK-3 inhibitor: induction of endoreplication following prophase arrest. Oncogene. 2001;20:3786–97.CrossRefPubMed
62.
Marko D, Schätzle S, Friedel A, Genzlinger A, Zankl H, Meijer L, Eisenbrand G. Inhibition of cyclin-dependent kinase 1 (CDK1) by indirubin derivatives in human tumour cells. Br J Cancer. 2001;84:283–9.PubMedCentralCrossRefPubMed
63.
Johnson DG, Walker CL. Cyclins and cell cycle checkpoints. Annu Rev Pharmacol Toxicol. 1999;39:295–312.CrossRefPubMed
Metadata
Title
Induction of atypical cell death in thyroid carcinoma cells by the indirubin derivative 7-bromoindirubin-3′-oxime (7BIO)
Authors
Martina Broecker-Preuss
Nina Becher-Boveleth
Susanne Gall
Katrin Rehmann
Susann Schenke
Klaus Mann
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2015
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-015-0251-8

Other articles of this Issue 1/2015

Cancer Cell International 1/2015 Go to the issue

Primary research

microRNA-30b inhibits cell invasion and migration through targeting collagen triple helix repeat containing 1 in non-small cell lung cancer

Primary research

Antitumoral potency of methanolic extract from Nitraria retusa leaves via its immunomodulatory effect

Review

Evaluating the evidence for targeting FOXO3a in breast cancer: a systematic review

Primary research

Jacaric acid inhibits the growth of murine macrophage-like leukemia PU5-1.8 cells by inducing cell cycle arrest and apoptosis

Primary research

RETRACTED ARTICLE: Down-regulation of miR-133a and miR-539 are associated with unfavorable prognosis in patients suffering from osteosarcoma

Primary research

EHMT2 inhibitor BIX-01294 induces apoptosis through PMAIP1-USP9X-MCL1 axis in human bladder cancer cells
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