Skip to main content
Hauptrubriken
CME Facharzt-Training Webinare Zeitschriften Bücher e.Medpedia Podcast
Service
Jobbörse Info & Hilfe
Fachgebiete
Anästhesiologie Allgemeinmedizin Arbeitsmedizin Augenheilkunde Chirurgie Dermatologie Gynäkologie und Geburtshilfe HNO Innere Medizin Kardiologie Neurologie Onkologie und Hämatologie Orthopädie und Unfallchirurgie Pädiatrie Pathologie Psychiatrie Radiologie Rechtsmedizin Urologie Zahnmedizin
Themen
Klimawandel und Gesundheit Neues aus dem Markt COVID-19 Praxis und Beruf Seltene Erkrankungen GOÄ & EBM Panorama
Sammlungen
Kasuistiken Algorithmen & Infografiken Blickdiagnosen Arthropedia FlapFinder (für Dermatochirurgen) Videos Kongressberichterstattung Medizin für Apothekerinnen und Apotheker Für Ärztinnen und Ärzte in Weiterbildung Für Medizinstudierende
Erweiterte Suche
Anmelden
nach oben
Inflammation Research
Erschienen in: Inflammation Research 10/2017

14.06.2017 | Original Research Paper

Di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), an anticancer agent, exerts an anti-inflammatory effect in activated human mast cells

verfasst von: Sun-Young Nam, Na-Ra Han, Kyoung Wan Yoon, Hyung-Min Kim, Hyun-Ja Jeong

Erschienen in: Inflammation Research | Ausgabe 10/2017

Einloggen, um Zugang zu erhalten

Abstract

Objective

Inflammation has been closely associated with the development and progression of cancer. Previously, we reported that mast cells play a critical role in tumor growth. The purpose of this study is to investigate the anti-inflammatory effect of an anticancer agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), on an activated human mast cell line, in this case HMC-1 cells.

Methods

We evaluated the effect and specific molecular mechanism of Dp44mT on phorbol 12-myristate 13-acetate and calcium ionophore A23187 (PMACI) using HMC-1 cells.

Results

Here, we demonstrated that Dp44mT significantly decreased the protein levels of hypoxia-inducible factor-1α and vascular endothelial growth factor without exposing activated HMC-1 cells to any cytotoxicity. In activated mast cells, Dp44mT mitigated the strong production and mRNA expression of inflammatory cytokines, in this case, interleukin (IL)-1β, IL-6, tumor necrosis factor-α, and thymic stromal lymphopoietin, through a blockade of caspase-1 and nuclear factor-κB activities. Furthermore, phosphorylations of the mitogen-activated protein kinase family included in inflammatory signaling cascades were significantly inhibited by a Dp44mT treatment.

Conclusions

Overall, our results indicate that the anticancer agent Dp44mT has an anti-inflammatory effect and may be of therapeutic importance for the treatment of mast cell-mediated inflammatory diseases.
Literatur
1.
Majno G, Joris I. Cells. Tissues and disease. 2nd ed. New York: Oxford University Press; 2004.
2.
Kumar V, Cotran RS, Robbins SL. Robbins basic pathology. 7th ed. Philadelphia: Saunders; 2003.
3.
4.
Rakoff-Nahoum S. Why cancer and inflammation? Yale J Biol Med. 2006;79(3–4):123–30.PubMed
5.
Chang HY, Sneddon JB, Alizadeh AA, Sood R, West RB, Montgomery K, et al. Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds. PLoS Biol. 2004;2(2):E7.CrossRefPubMedPubMedCentral
6.
Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313(5795):1960–4.CrossRefPubMed
7.
8.
Wang WS, Chen PM, Wang HS, Liang WY, Su Y. Matrix metalloproteinase-7 increases resistance to Fas-mediated apoptosis and is a poor prognostic factor of patients with colorectal carcinoma. Carcinogenesis. 2006;27(5):1113–20.CrossRefPubMed
9.
de Visser KE, Eichten A, Coussens LM. Paradoxical roles of the immune system during cancer development. Nat Rev Cancer. 2006;6(1):24–37.CrossRefPubMed
10.
Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357(9255):539–45.CrossRefPubMed
11.
Condeelis J, Pollard JW. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell. 2006;124(2):263–6.CrossRefPubMed
12.
Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002;2(3):161–74.CrossRefPubMed
13.
Jeong HJ, Oh HA, Nam SY, Han NR, Kim YS, Kim JH, et al. The critical role of mast cell-derived hypoxia-inducible factor-1α in human and mice melanoma growth. Int J Cancer. 2013;132(11):2492–501.CrossRefPubMed
14.
Karin M, Greten FR. NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 2005;5(10):749–59.CrossRefPubMed
15.
16.
Yoshida K, Ito M, Matsuoka I. Divergent regulatory roles of extracellular ATP in the degranulation response of mouse bone marrow-derived mast cells. Int Immunopharmacol. 2016;43:99–107.CrossRefPubMed
17.
Han NR, Oh HA, Nam SY, Moon PD, Kim DW, Kim HM, et al. TSLP induces mast cell development and aggravates allergic reactions through the activation of MDM2 and STAT6. J Invest Dermatol. 2014;134(10):2521–30.CrossRefPubMed
18.
Jeong HJ, Koo HN, Na HJ, Kim MS, Hong SH, Eom JW, et al. Inhibition of TNF-alpha and IL-6 production by Aucubin through blockade of NF-kappaB activation RBL-2H3 mast cells. Cytokine. 2002;18(5):252–9.CrossRefPubMed
19.
20.
Guo ZL, Richardson DR, Kalinowski DS, Kovacevic Z, Tan-Un KC, Chan GC. The novel thiosemicarbazone, di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), inhibits neuroblastoma growth in vitro and in vivo via multiple mechanisms. J Hematol Oncol. 2016;9(1):98.CrossRefPubMedPubMedCentral
21.
Li P, Zheng X, Shou K, Niu Y, Jian C, Zhao Y, et al. The iron chelator Dp44mT suppresses osteosarcoma’s proliferation, invasion and migration: in vitro and in vivo. Am J Transl Res. 2016;8(12):5370–85.PubMedPubMedCentral
22.
Merlot AM, Pantarat N, Menezes SV, Sahni S, Richardson DR, Kalinowski DS. Cellular uptake of the antitumor agent Dp44mT occurs via a carrier/receptor-mediated mechanism. Mol Pharmacol. 2013;84(6):911–24.CrossRefPubMed
23.
Yuan J, Lovejoy DB, Richardson DR. Novel di-2-pyridyl-derived iron chelators with marked and selective antitumor activity: in vitro and in vivo assessment. Blood. 2004;104(5):1450–8.CrossRefPubMed
24.
Whitnall M, Howard J, Ponka P, Richardson DR. A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics. Proc Natl Acad Sci USA. 2006;103(40):14901–6.CrossRefPubMedPubMedCentral
25.
Jansson PJ, Yamagishi T, Arvind A, Seebacher N, Gutierrez E, Stacy A, et al. Di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) overcomes multidrug resistance by a novel mechanism involving the hijacking of lysosomal P-glycoprotein (Pgp). J Biol Chem. 2015;290(15):9588–603.CrossRefPubMedPubMedCentral
26.
Merlot AM, Sahni S, Lane DJ, Fordham AM, Pantarat N, Hibbs DF, et al. Potentiating the cellular targeting and anti-tumor activity of Dp44mT via binding to human serum albumin: two saturable mechanisms of Dp44mT uptake by cells. Oncotarget. 2015;6(12):10374–98.CrossRefPubMedPubMedCentral
27.
Kovacevic Z, Chikhani S, Lovejoy DB, Richardson DR. Novel thiosemicarbazone iron chelators induce up-regulation and phosphorylation of the metastasis suppressor N-myc down-stream regulated gene 1: a new strategy for the treatment of pancreatic cancer. Mol Pharmacol. 2011;80(4):598–609.CrossRefPubMed
28.
Krishan S, Richardson DR, Sahni S. The anticancer agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), up-regulates the AMPK-dependent energy homeostasis pathway in cancer cells. Biochim Biophys Acta. 2016;1863(12):2916–33.CrossRefPubMed
29.
Merlot AM, Shafie NH, Yu Y, Richardson V, Jansson PJ, Sahni S, et al. Mechanism of the induction of endoplasmic reticulum stress by the anti-cancer agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT): activation of PERK/eIF2α, IRE1α, ATF6 and calmodulin kinase. Biochem Pharmacol. 2016;109:27–47.CrossRefPubMed
30.
Kim EJ, Kim MH. Anti-oxidant and anti-inflammatory effects of Salix koreensis Andersson in DC. Leaf methanol extract in vitro models. TANG. 2016;6:e23.
31.
Jeong HJ, Chung HS, Lee BR, Kim SJ, Yoo SJ, Hong SH, et al. Expression of proinflammatory cytokines via HIF-1alpha and NF-kappaB activation on desferrioxamine-stimulated HMC-1 cells. Biochem Biophys Res Commun. 2003;306(4):805–11.CrossRefPubMed
32.
33.
Waldner MJ, Neurath MF. Colitis-associated cancer: the role of T cells in tumor development. Semin Immunopathol. 2009;31(2):249–56.CrossRefPubMed
34.
Karin M. Nuclear factor-kappaB in cancer development and progression. Nature. 2006;441(7092):431–6.CrossRefPubMed
35.
Wu S, Rhee KJ, Albesiano E, Rabizadeh S, Wu X, Yen HR, et al. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med. 2009;15(9):1016–22.CrossRefPubMedPubMedCentral
36.
Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ, et al. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell. 2004;118(3):285–96.CrossRefPubMed
37.
Jin H, Jin X, Cao B, Wang W. Berberine affects osteosarcoma via downregulating the caspase-1/IL-1β signaling axis. Oncol Rep. 2017;37(2):729–36.CrossRefPubMed
38.
Seol MA, Park JH, Jeong JH, Lyu J, Han SY, Oh SM. Role of TOPK in lipopolysaccharide-induced breast cancer cell migration and invasion. Oncotarget. 2017. doi:10.​18632/​oncotarget.​15360.
39.
40.
Grandjean G, de Jong PR, James BP, Koh MY, Lemos R, Kingston J, et al. Definition of a novel feed-forward mechanism for glycolysis-HIF1α signaling in hypoxic tumors highlights aldolase A as a therapeutic target. Cancer Res. 2016;76(14):4259–69.CrossRefPubMedPubMedCentral
41.
Takahashi N, Sugaya M, Suga H, Oka T, Kawaguchi M, Miyagaki T, et al. Thymic stromal chemokine TSLP acts through Th2 cytokine production to induce cutaneous T-cell lymphoma. Cancer Res. 2016;76(21):6241–52.CrossRefPubMed
42.
Tu S, Bhagat G, Cui G, Takaishi S, Kurt-Jones EA, Rickman B, et al. Overexpression of interleukin-1beta induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. Cancer Cell. 2008;14(5):408–19.CrossRefPubMedPubMedCentral
43.
Wong VW, Yu J, Cheng AS, Wong GL, Chan HY, Chu ES, et al. High serum interleukin-6 level predicts future hepatocellular carcinoma development in patients with chronic hepatitis B. Int J Cancer. 2009;124(12):2766–70.CrossRefPubMed
44.
Becker C, Fantini MC, Schramm C, Lehr HA, Wirtz S, Nikolaev A, et al. TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling. Immunity. 2004;21(4):491–501.CrossRefPubMed
45.
Grivennikov S, Karin E, Terzic J, Mucida D, Yu GY, Vallabhapurapu S, et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell. 2009;15(2):103–13.CrossRefPubMedPubMedCentral
46.
Hedvat M, Huszar D, Herrmann A, Gozgit JM, Schroeder A, Sheehy A, et al. The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors. Cancer Cell. 2009;16(6):487–97.CrossRefPubMedPubMedCentral
Metadaten
Titel
Di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), an anticancer agent, exerts an anti-inflammatory effect in activated human mast cells
verfasst von
Sun-Young Nam
Na-Ra Han
Kyoung Wan Yoon
Hyung-Min Kim
Hyun-Ja Jeong
Publikationsdatum
14.06.2017
Verlag
Springer International Publishing
Erschienen in
Inflammation Research / Ausgabe 10/2017
Print ISSN: 1023-3830
Elektronische ISSN: 1420-908X
DOI
https://doi.org/10.1007/s00011-017-1067-x

Weitere Artikel der Ausgabe 10/2017

Inflammation Research 10/2017 Zur Ausgabe

Review

“Inflammatory skin march” in atopic dermatitis and psoriasis

Original Research Paper

Pam2CSK4 and Pam3CSK4 induce iNOS expression via TBK1 and MyD88 molecules in mouse macrophage cell line RAW264.7

Original Research Paper

From medicinal plant extracts to defined chemical compounds targeting the histamine H4 receptor: Curcuma longa in the treatment of inflammation

Original Research Paper

Delta neutrophil index (DNI) as a novel diagnostic and prognostic marker of infection: a systematic review and meta-analysis

Original Research Paper

2K1C-activated Angiotensin II (Ang II) exacerbates vascular damage in a rat model of arthritis through the ATR/ERK1/2 signaling pathway

Original Research Paper

Effects of sevoflurane on NF-кB and TNF-α expression in renal ischemia–reperfusion diabetic rats

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Notfall-TEP der Hüfte ist auch bei 90-Jährigen machbar

26.04.2024 Hüft-TEP Nachrichten

Ob bei einer Notfalloperation nach Schenkelhalsfraktur eine Hemiarthroplastik oder eine totale Endoprothese (TEP) eingebaut wird, sollte nicht allein vom Alter der Patientinnen und Patienten abhängen. Auch über 90-Jährige können von der TEP profitieren.

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

25.04.2024 Hypotonie Nachrichten

Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.

Bei schweren Reaktionen auf Insektenstiche empfiehlt sich eine spezifische Immuntherapie

25.04.2024 Allergien und Intoleranzreaktionen Nachrichten

Insektenstiche sind bei Erwachsenen die häufigsten Auslöser einer Anaphylaxie. Einen wirksamen Schutz vor schweren anaphylaktischen Reaktionen bietet die allergenspezifische Immuntherapie. Jedoch kommt sie noch viel zu selten zum Einsatz.

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

25.04.2024 Hypertonie Nachrichten

Beginnen ältere Männer im Pflegeheim eine Antihypertensiva-Therapie, dann ist die Frakturrate in den folgenden 30 Tagen mehr als verdoppelt. Besonders häufig stürzen Demenzkranke und Männer, die erstmals Blutdrucksenker nehmen. Dafür spricht eine Analyse unter US-Veteranen.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen
Bildnachweise