{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T14:43:39Z","timestamp":1792507419041,"version":"4.5.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2019,7,3]],"date-time":"2019-07-03T00:00:00Z","timestamp":1562112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"DOI":"10.3389\/fonc.2019.00605","type":"journal-article","created":{"date-parts":[[2019,7,3]],"date-time":"2019-07-03T10:20:41Z","timestamp":1562149241000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":24,"title":["Topical Diclofenac Reprograms Metabolism and Immune Cell Infiltration in Actinic Keratosis"],"prefix":"10.3389","volume":"9","author":[{"given":"Katrin","family":"Singer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Dettmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Unger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Sch\u00f6nhammer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrin","family":"Renner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin","family":"Peter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Siska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Berneburg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Herr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Oefner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sigrid","family":"Karrer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Kreutz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Datz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2019,7,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1111\/j.1365-2133.2005.07121.x","article-title":"Solar (actinic) keratosis is squamous cell carcinoma","volume":"155","author":"Ackerman","year":"2006","journal-title":"Br J Dermatol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1111\/jdv.12102","article-title":"Prevalence and risk factors of actinic keratoses in Germany\u2013analysis of multisource data","volume":"28","author":"Schaefer","year":"2014","journal-title":"J Eur Acad Dermatol Venereol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1971","DOI":"10.1038\/jid.2013.134","article-title":"Prevalence of actinic keratosis and its risk factors in the general population: the Rotterdam study","volume":"133","author":"Flohil","year":"2013","journal-title":"J Invest Dermatol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1159\/000366525","article-title":"Epidemiology of actinic keratoses","volume":"46","author":"Green","year":"2015","journal-title":"Curr Probl Dermatol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.1111\/j.1610-0387.2011.07700.x","article-title":"Modes of action of diclofenac 3%\/hyaluronic acid 2","volume":"9","author":"Maltusch","year":"2011","journal-title":"J Dtsch Dermatol Ges."},{"key":"B6","doi-asserted-by":"publisher","first-page":"2098","DOI":"10.1038\/jid.2010.40","article-title":"Enhanced death ligand-induced apoptosis in cutaneous SCC cells by treatment with diclofenac\/hyaluronic acid correlates with downregulation of c-FLIP","volume":"130","author":"Fecker","year":"2010","journal-title":"J Invest Dermatol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"381","DOI":"10.5603\/FHC.2011.0054","article-title":"Different expression of cyclooxygenase-2 (COX-2) in selected nonmelanocytic human cutaneous lesions","volume":"49","author":"Kuzbicki","year":"2011","journal-title":"Folia Histochem Cytobiol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1111\/j.1468-3083.2011.04005.x","article-title":"Open label randomized study comparing 3 months vs","volume":"26","author":"Pflugfelder","year":"2012","journal-title":"J Eur Acad Dermatol Venereol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"610","DOI":"10.3332\/ecancer.2016.610","article-title":"Repurposing drugs in oncology (ReDO)-diclofenac as an anti-cancer agent","volume":"10","author":"Pantziarka","year":"2016","journal-title":"Ecancermedicalscience."},{"key":"B10","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1111\/j.1600-0625.2012.01516.x","article-title":"Activation of mitochondrial apoptosis pathways in cutaneous squamous cell carcinoma cells by diclofenac\/hyaluronic acid is related to upregulation of Bad as well as downregulation of Mcl-1 and Bcl-w","volume":"21","author":"Rodust","year":"2012","journal-title":"Exp Dermatol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"207","DOI":"10.2147\/TCRM.S12498","article-title":"Diclofenac gel in the treatment of actinic keratoses","volume":"7","author":"Nelson","year":"2011","journal-title":"Ther Clin Risk Manag."},{"key":"B12","doi-asserted-by":"publisher","first-page":"e66987","DOI":"10.1371\/journal.pone.0066987","article-title":"New aspects of an old drug\u2013diclofenac targets MYC and glucose metabolism in tumor cells","volume":"8","author":"Gottfried","year":"2013","journal-title":"PLoS ONE."},{"key":"B13","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1002\/ijc.27712","article-title":"Diclofenac inhibits lactate formation and efficiently counteracts local immune suppression in a murine glioma model","volume":"132","author":"Chirasani","year":"2013","journal-title":"Int J Cancer."},{"key":"B14","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1085\/jgp.8.6.519","article-title":"The metabolism of tumors in the body","volume":"8","author":"Warburg","year":"1927","journal-title":"J Gen Physiol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"248","DOI":"10.3389\/fimmu.2017.00248","article-title":"Metabolic hallmarks of tumor and immune cells in the tumor microenvironment","volume":"8","author":"Renner","year":"2017","journal-title":"Front Immunol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1242\/dmm.034272","article-title":"Immunometabolism in cancer at a glance","volume":"11","author":"Singer","year":"2018","journal-title":"Dis Model Mech."},{"key":"B17","doi-asserted-by":"publisher","first-page":"3812","DOI":"10.1182\/blood-2006-07-035972","article-title":"Inhibitory effect of tumor cell-derived lactic acid on human T cells","volume":"109","author":"Fischer","year":"2007","journal-title":"Blood."},{"key":"B18","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1016\/j.cmet.2016.08.011","article-title":"LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells","volume":"24","author":"Brand","year":"2016","journal-title":"Cell Metab."},{"key":"B19","doi-asserted-by":"publisher","first-page":"2013","DOI":"10.1182\/blood-2005-05-1795","article-title":"Tumor-derived lactic acid modulates dendritic cell activation and antigen expression","volume":"107","author":"Gottfried","year":"2006","journal-title":"Blood."},{"key":"B20","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1016\/S0360-3016(01)01630-3","article-title":"Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer","volume":"51","author":"Brizel","year":"2001","journal-title":"Int J Radiat Oncol Biol Phys."},{"key":"B21","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.drup.2016.09.003","article-title":"The reduced concentration of citrate in cancer cells: An indicator of cancer aggressiveness and a possible therapeutic target","volume":"29","author":"Icard","year":"2016","journal-title":"Drug Resist Updat."},{"key":"B22","doi-asserted-by":"crossref","DOI":"10.1111\/j.1365-2133.2007.07860.x","article-title":"Actinic keratosis is an early in situ squamous cell carcinoma: a proposal for reclassification","volume-title":"Br J Dermatol.","author":"Rowert-Huber","year":"2007"},{"key":"B23","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1111\/j.1365-2133.2012.10887.x","article-title":"Clinical, histopathological and immunohistochemical assessment of human skin field cancerization before and after photodynamic therapy","volume":"167","author":"Szeimies","year":"2012","journal-title":"Br J Dermatol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"3249","DOI":"10.1007\/s00216-011-5436-y","article-title":"Quantitative profiling of tryptophan metabolites in serum, urine, and cell culture supernatants by liquid chromatography-tandem mass spectrometry","volume":"401","author":"Zhu","year":"2011","journal-title":"Anal Bioanal Chem."},{"key":"B25","doi-asserted-by":"publisher","first-page":"14912","DOI":"10.1073\/pnas.1203083109","article-title":"Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation","volume":"109","author":"van der","year":"2012","journal-title":"Proc Natl Acad Sci USA."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.1007\/s00216-010-4425-x","article-title":"Metabolite extraction from adherently growing mammalian cells for metabolomics studies: optimization of harvesting and extraction protocols","volume":"399","author":"Dettmer","year":"2011","journal-title":"Anal Bioanal Chem."},{"key":"B27","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1038\/nrc2809","article-title":"Eicosanoids and cancer","volume":"10","author":"Wang","year":"2010","journal-title":"Nat Rev Cancer."},{"key":"B28","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1038\/nrc3245","article-title":"The immune contexture in human tumours: impact on clinical outcome","volume":"12","author":"Fridman","year":"2012","journal-title":"Nat Rev Cancer."},{"key":"B29","doi-asserted-by":"publisher","first-page":"e33615","DOI":"10.1371\/journal.pone.0033615","article-title":"Down-regulation of glucose-regulated protein (GRP) 78 potentiates cytotoxic effect of celecoxib in human urothelial carcinoma cells","volume":"7","author":"Huang","year":"2012","journal-title":"PLoS ONE."},{"key":"B30","doi-asserted-by":"publisher","first-page":"584","DOI":"10.18632\/oncotarget.965","article-title":"Dysfunctional oxidative phosphorylation makes malignant melanoma cells addicted to glycolysis driven by the (V600E)BRAF oncogene","volume":"4","author":"Hall","year":"2013","journal-title":"Oncotarget."},{"key":"B31","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1016\/S0190-9622(97)70174-9","article-title":"Expression of the human erythrocyte glucose transporter Glut1 in cutaneous neoplasia","volume":"37","author":"Baer","year":"1997","journal-title":"J Am Acad Dermatol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1258","DOI":"10.3389\/fphar.2018.01258","article-title":"Combined metabolic targeting with metformin and the NSAIDs diflunisal and diclofenac induces apoptosis in acute myeloid leukemia cells","volume":"9","author":"Renner","year":"2018","journal-title":"Front Pharmacol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1684\/ejd.2010.1010","article-title":"Results of a randomized, placebo-controlled safety and efficacy study of topical diclofenac 3% gel in organ transplant patients with multiple actinic keratoses","volume":"20","author":"Ulrich","year":"2010","journal-title":"Eur J Dermatol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1229","DOI":"10.1016\/j.cell.2015.08.016","article-title":"Metabolic competition in the tumor microenvironment is a driver of cancer progression","volume":"162","author":"Chang","year":"2015","journal-title":"Cell."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1016\/j.cell.2015.08.012","article-title":"Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses","volume":"162","author":"Ho","year":"2015","journal-title":"Cell."},{"key":"B36","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1111\/j.1600-0625.2006.00505.x","article-title":"Non-steroidal anti-inflammatory drugs selectively inhibit cytokine production by NK cells and gamma delta T cells","volume":"15","author":"Inaoka","year":"2006","journal-title":"Exp Dermatol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1016\/j.cell.2017.01.016","article-title":"The principles of engineering immune cells to treat cancer","volume":"168","author":"Lim","year":"2017","journal-title":"Cell."},{"key":"B38","doi-asserted-by":"publisher","first-page":"5341","DOI":"10.1158\/1078-0432.CCR-12-1985","article-title":"EWS-FLI-1-targeted cytotoxic T-cell killing of multiple tumor types belonging to the Ewing sarcoma family of tumors","volume":"18","author":"Evans","year":"2012","journal-title":"Clin Cancer Res."},{"key":"B39","doi-asserted-by":"publisher","first-page":"e0160096","DOI":"10.1371\/journal.pone.0160096","article-title":"Tumor-preferential induction of immune responses and epidermal cell death in actinic keratoses by ingenol mebutate","volume":"11","author":"Emmert","year":"2016","journal-title":"PLoS ONE."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1002","DOI":"10.1111\/ddg.13614","article-title":"Nonmelanoma skin cancer - from actinic keratosis to cutaneous squamous cell carcinoma","volume":"16","author":"Schmitz","year":"2018","journal-title":"J Dtsch Dermatol Ges."},{"key":"B41","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1146\/annurev.immunol.19.1.683","article-title":"Interleukin-10 and the interleukin-10 receptor","volume":"19","author":"Moore","year":"2001","journal-title":"Annu Rev Immunol."},{"key":"B42","first-page":"34","article-title":"Number of Langerhans cells is decreased in premalignant keratosis and skin cancers","volume":"36","author":"Shevchuk","year":"2014","journal-title":"Exp Oncol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1111\/j.1600-0560.2008.01139.x","article-title":"Stromal CD10 expression, as well as increased dermal macrophages and decreased Langerhans cells, are associated with malignant transformation of keratinocytes","volume":"36","author":"Takahara","year":"2009","journal-title":"J Cutan Pathol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1016\/j.cell.2016.12.039","article-title":"Understanding the Intersections between metabolism and cancer biology","volume":"168","author":"Vander","year":"2017","journal-title":"Cell."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1296","DOI":"10.1038\/s41467-019-09179-w","article-title":"Targeting glutamine-addiction and overcoming CDK4\/6 inhibitor resistance in human esophageal squamous cell carcinoma","volume":"10","author":"Qie","year":"2019","journal-title":"Nat Commun."},{"key":"B46","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1016\/j.bbrc.2017.03.120","article-title":"Disturbed tryptophan metabolism correlating to progression and metastasis of esophageal squamous cell carcinoma","volume":"486","author":"Cheng","year":"2017","journal-title":"Biochem Biophys Res Commun."},{"key":"B47","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1016\/j.jdermsci.2004.08.012","article-title":"Gene expression of enzymes for tryptophan degradation pathway is upregulated in the skin lesions of patients with atopic dermatitis or psoriasis","volume":"36","author":"Ito","year":"2004","journal-title":"J Dermatol Sci."},{"key":"B48","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1158\/2326-6066.CIR-16-0400","article-title":"Constitutive IDO1 expression in human tumors is driven by cyclooxygenase-2 and mediates intrinsic immune resistance","volume":"5","author":"Hennequart","year":"2017","journal-title":"Cancer Immunol Res."}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/article\/10.3389\/fonc.2019.00605\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,7,3]],"date-time":"2019-07-03T10:20:43Z","timestamp":1562149243000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/article\/10.3389\/fonc.2019.00605\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,3]]},"references-count":48,"alternative-id":["10.3389\/fonc.2019.00605"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2019.00605","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,7,3]]},"article-number":"605"}}