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Gil da Costa, Rui M.; Levesque, Christine; Bianchi‐Frias, Daniella; Chatterjee, Payel; Lam, Hung‐Ming; Santos, Carlos; Coleman, Ilsa M.; Ferreirinha, Pedro; Vilanova, Manuel; Pinto da Cunha, Nazaré; Carvalho, Hugo; Moreira‐Pais, Alexandra; Faustino‐Rocha, Ana; Neto, Tiago; Batista da Costa, José; Wright, Jonathan L.; Ferreira, Rita; Oliveira, Paula A.; Mendes, Joaquim; Bastos, Margarida M. S. M.; Colaço, Bruno; Lopes, Carlos; Black, Peter C.; Sweeney, Christopher J.;

Pharmacological NF‐κB inhibition decreases cisplatin chemoresistance in muscle‐invasive bladder cancer and reduces cisplatin‐induced toxicities

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  • Medientyp: E-Artikel
  • Titel: Pharmacological NF‐κB inhibition decreases cisplatin chemoresistance in muscle‐invasive bladder cancer and reduces cisplatin‐induced toxicities
  • Beteiligte: Gil da Costa, Rui M.; Levesque, Christine; Bianchi‐Frias, Daniella; Chatterjee, Payel; Lam, Hung‐Ming; Santos, Carlos; Coleman, Ilsa M.; Ferreirinha, Pedro; Vilanova, Manuel; Pinto da Cunha, Nazaré; Carvalho, Hugo; Moreira‐Pais, Alexandra; Faustino‐Rocha, Ana; Neto, Tiago; Batista da Costa, José; Wright, Jonathan L.; Ferreira, Rita; Oliveira, Paula A.; Mendes, Joaquim; Bastos, Margarida M. S. M.; Colaço, Bruno; Lopes, Carlos; Black, Peter C.; Sweeney, Christopher J.;
  • Erschienen: Wiley, 2023
  • Erschienen in: Molecular Oncology
  • Sprache: Englisch
  • DOI: 10.1002/1878-0261.13504
  • ISSN: 1574-7891; 1878-0261
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:p>Most patients with muscle‐invasive bladder cancer (MIBC) are not cured with platinum chemotherapy. Up‐regulation of nuclear factor kappa light‐chain enhancer of activated B cells (NF‐κB) is a major mechanism underlying chemoresistance, suggesting that its pharmacological inhibition may increase platinum efficacy. NF‐κB signaling was investigated in two patient cohorts. The Cancer Genome Atlas (TCGA) was used to correlate NF‐κB signaling and patient survival. The efficacy of cisplatin plus the NF‐κB inhibitor dimethylaminoparthenolide (DMAPT) versus cisplatin or DMAPT alone was tested <jats:italic>in vitro</jats:italic>. Xenografted and immunocompetent MIBC mouse models were studied <jats:italic>in vivo</jats:italic>. Platinum‐naive claudin‐low MIBC showed constitutive NF‐κB signaling and this was associated with reduced disease‐specific survival in TCGA patients. Chemotherapy up‐regulated NF‐κB signaling and chemoresistance‐associated genes, including <jats:italic>SPHK1</jats:italic>, <jats:italic>PLAUR,</jats:italic> and <jats:italic>SERPINE1</jats:italic>. In mice, DMAPT significantly improved the efficacy of cisplatin in both models. The combination preserved body weight, renal function, and morphology, reduced muscle fatigue and IL‐6 serum levels, and did not aggravate immuno‐hematological toxicity compared with cisplatin alone. These data provide a rationale for combining NF‐κB inhibition with platinum‐based chemotherapy and conducting a clinical trial in MIBC patients.</jats:p>
  • Zugangsstatus: Freier Zugang