{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2022,6,25]],"date-time":"2022-06-25T00:14:47Z","timestamp":1656116087527},"reference-count":0,"publisher":"American Association for Cancer Research (AACR)","issue":"13_Supplement","content-domain":{"domain":["aacrjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>BACKGROUND: Nuclear factor kappaB (NF-\u03baB) blocks apoptosis and promotes chemoresistance to drugs like cisplatin (CDDP). However, the clinical use of NF-\u03baB inhibitors is restricted to hematological malignancies and the benefit of NF-\u03baB inhibition in solid tumors has yet to be realized. The novel agent dimethylaminoparthenolide (DMAPT) blocks NF-\u03baB in bladder cancer cell lines and can overcome chemoresistance as part of a combination therapy. METHODS AND RESULTS: We tested DMAPT's ability to enhance CDDP's efficacy against muscle-invasive bladder cancer. In vitro, 2.5 \u00b5M DMAPT was shown to up-regulate death receptor 4 and 5 expression and induce poly (ADP-ribose) polymerase (PARP) cleavage in UMUC-3 cells. Both 2.5 \u00b5M DMAPT and 2.5 \u00b5M CDDP reduced UMUC-3 cell viability as single agents, and their effect was enhanced when combined. We next tested CDDP (4.0 mg\/kg\/week i.p) and DMAPT (100.0 mg\/kg\/day oral) in combination and as single agents for 6 weeks in an immune-competent mouse model of muscle-invasive (T2) bladder cancer induced by the tobacco-related agent N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN). Procedures followed the 2010\/63\/EU animal welfare directive. One DMAPT-treated and 1 CDDP-treated mouse died during the experiments. The cohorts were: negative control (no BBN exposure, n=15), positive control (BBN but no therapy, n=19), BBN and DMAPT-treated (n=17), BBN and CDDP-treated (n=18) and BBN and the combination of CDDP plus DMAPT (n=19). Negative control, positive control, DMAPT, CDDP and combination-treated mice showed 0.0%, 42.1%, 35.3%, 11.1% and 0.0% bladder cancer incidence, respectively. T2 (muscle-invasive) lesions were present in positive controls (15.8%), DMAPT (17.6%) and CDDP (5.6%), but not in the combination group (0.0%). High-grade urothelial dysplasia, a pre-malignant lesion, was observed at rates of: 57.9% (positive controls), 29.4% (DMAPT), 16.6% (CDDP) and 0.0% (combination). CDDP induced renal tubular necrosis and interstitial nephritis seen on H&amp;E with increased urea (BUN) and creatinine. The combination therapy reduced interstitial nephritis, BUN (p&amp;lt;0.05, Student's t test) and creatinine levels. CDDP reduced gastrocnemius muscle mass, increased muscular fatigue (grip strength test) and reduced body weight. These effects were ameliorated in combination-treated mice. CDDP and the combination therapy induced anemia and atrophy of bone marrow, thymus and spleen at identical levels. CONCLUSION: The DMAPT-CDDP combination was more effective than CDDP as single agent in vitro and in vivo, and totally eradicated malignant and pre-malignant bladder lesions in an immune-competent mouse model. The combination ameliorated CDDP-induced nephrotoxicity and muscle wasting presumably by blocking CDDP mediated injury from NF-\u03baB activation in normal tissues, without imposing additional hematological toxicity.<\/jats:p>\n               <jats:p>Citation Format: Rui M. Gil da Costa, Pedro Ferreirinha, Nazar\u00e9 Pinto da Cunha, Carlos Santos, Tiago Neto, Ana I. Faustino-Rocha, Manuel Vilanova, Margarida M. Bastos, Carlos Lopes, Paula A. Oliveira, Joaquim Gabriel, Peter Nelson, Christopher Sweeney. NF-kB inhibitor DMAPT enhances cisplatin efficacy and reduces its toxicity in a carcinogen-induced model of muscle-invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4047. doi:10.1158\/1538-7445.AM2017-4047<\/jats:p>","DOI":"10.1158\/1538-7445.am2017-4047","type":"journal-article","created":{"date-parts":[[2017,7,31]],"date-time":"2017-07-31T21:43:48Z","timestamp":1501537428000},"page":"4047-4047","update-policy":"http:\/\/dx.doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Abstract 4047: NF-kB inhibitor DMAPT enhances cisplatin efficacy and reduces its toxicity in a carcinogen-induced model of muscle-invasive bladder cancer"],"prefix":"10.1158","volume":"77","author":[{"given":"Rui M. Gil da","family":"Costa","sequence":"first","affiliation":[{"name":"1University of Porto, Porto, Portugal;"}]},{"given":"Pedro","family":"Ferreirinha","sequence":"additional","affiliation":[{"name":"1University of Porto, Porto, Portugal;"}]},{"given":"Nazar\u00e9 Pinto da","family":"Cunha","sequence":"additional","affiliation":[{"name":"2CEDIVET - Veterinary Diagnostic Center, Porto, Portugal;"}]},{"given":"Carlos","family":"Santos","sequence":"additional","affiliation":[{"name":"1University of Porto, Porto, Portugal;"}]},{"given":"Tiago","family":"Neto","sequence":"additional","affiliation":[{"name":"1University of Porto, Porto, Portugal;"}]},{"given":"Ana I.","family":"Faustino-Rocha","sequence":"additional","affiliation":[{"name":"3CITAB, University of Tr\u00e1s-os-Montes and Alto Douro, Vila Real, Portugal;"}]},{"given":"Manuel","family":"Vilanova","sequence":"additional","affiliation":[{"name":"1University of Porto, Porto, Portugal;"}]},{"given":"Margarida M.","family":"Bastos","sequence":"additional","affiliation":[{"name":"1University of Porto, Porto, Portugal;"}]},{"given":"Carlos","family":"Lopes","sequence":"additional","affiliation":[{"name":"4Portuguese Institute of Oncology, Porto, Portugal;"}]},{"given":"Paula A.","family":"Oliveira","sequence":"additional","affiliation":[{"name":"3CITAB, University of Tr\u00e1s-os-Montes and Alto Douro, Vila Real, Portugal;"}]},{"given":"Joaquim","family":"Gabriel","sequence":"additional","affiliation":[{"name":"1University of Porto, Porto, Portugal;"}]},{"given":"Peter","family":"Nelson","sequence":"additional","affiliation":[{"name":"5Fred Hutchinson Cancer Research Center, Seattle, WA;"}]},{"given":"Christopher","family":"Sweeney","sequence":"additional","affiliation":[{"name":"6Dana-Farber Cancer Institute, Boston, MA."}]}],"member":"1086","container-title":["Cancer Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/aacrjournals.org\/cancerres\/article\/77\/13_Supplement\/4047\/619783\/Abstract-4047-NF-kB-inhibitor-DMAPT-enhances","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/aacrjournals.org\/cancerres\/article\/77\/13_Supplement\/4047\/619783\/Abstract-4047-NF-kB-inhibitor-DMAPT-enhances","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,24]],"date-time":"2022-06-24T23:51:38Z","timestamp":1656114698000},"score":1,"resource":{"primary":{"URL":"https:\/\/aacrjournals.org\/cancerres\/article\/77\/13_Supplement\/4047\/619783\/Abstract-4047-NF-kB-inhibitor-DMAPT-enhances"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,7,1]]},"references-count":0,"journal-issue":{"issue":"13_Supplement","published-print":{"date-parts":[[2017,7,1]]}},"URL":"https:\/\/doi.org\/10.1158\/1538-7445.am2017-4047","relation":{},"ISSN":["0008-5472","1538-7445"],"issn-type":[{"value":"0008-5472","type":"print"},{"value":"1538-7445","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,7,1]]}}}