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Abstract 4047: NF-kB inhibitor DMAPT enhances cisplatin efficacy and reduces its toxicity in a carcinogen-induced model of muscle-invasive bladder cancer

2017; American Association for Cancer Research; Volume: 77; Issue: 13_Supplement Linguagem: Inglês

10.1158/1538-7445.am2017-4047

1538-7445

Rui M. Gil da Costa, Pedro Ferreirinha, Nazaré Pinto da Cunha, Carlos Santos, Tiago Neto, Ana I. Faustino‐Rocha, Manuel Vilanova, Margarida M. S. M. Bastos, Carlos Lopes, Paula A. Oliveira, Joaquim Mendes, Peter S. Nelson, Christopher J. Sweeney,

Cancer, Stress, Anesthesia, and Immune Response

Abstract BACKGROUND: Nuclear factor kappaB (NF-κB) blocks apoptosis and promotes chemoresistance to drugs like cisplatin (CDDP). However, the clinical use of NF-κB inhibitors is restricted to hematological malignancies and the benefit of NF-κB inhibition in solid tumors has yet to be realized. The novel agent dimethylaminoparthenolide (DMAPT) blocks NF-κB 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 µM 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 µM DMAPT and 2.5 µM 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&E with increased urea (BUN) and creatinine. The combination therapy reduced interstitial nephritis, BUN (p<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-κB activation in normal tissues, without imposing additional hematological toxicity. Citation Format: Rui M. Gil da Costa, Pedro Ferreirinha, Nazaré 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