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
Inflammation Research
Published in: Inflammation Research 10/2017

01-10-2017 | 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

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

Published in: Inflammation Research | Issue 10/2017

Login to get access

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.
Literature
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.
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
Metadata
Title
Di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), an anticancer agent, exerts an anti-inflammatory effect in activated human mast cells
Authors
Sun-Young Nam
Na-Ra Han
Kyoung Wan Yoon
Hyung-Min Kim
Hyun-Ja Jeong
Publication date
01-10-2017
Publisher
Springer International Publishing
Published in
Inflammation Research / Issue 10/2017
Print ISSN: 1023-3830
Electronic ISSN: 1420-908X
DOI
https://doi.org/10.1007/s00011-017-1067-x

Other articles of this Issue 10/2017

Inflammation Research 10/2017 Go to the issue

Original Research Paper

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

Original Research Paper

Anti-allodynic action of the disease-modifying anti-rheumatic drug iguratimod in a rat model of neuropathic pain

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

Resveratrol alleviates inflammatory hyperalgesia by modulation of reactive oxygen species (ROS), antioxidant enzymes and ERK activation

Review

“Inflammatory skin march” in atopic dermatitis and psoriasis

Original Research Paper

Endocytosis is required for exocytosis and priming of respiratory burst activity in human neutrophils
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits