Pharmacological NF-?B inhibition decreases cisplatin chemoresistance in muscle-invasive bladder cancer and reduces cisplatin-induced toxicities.

• Type: Article in International Scientific Journal
• Date: 2023

Authors

da Costa, RMG (Author) Other; Levesque, C (Author) Other; Bianchi-Frias, D (Author) Other; Chatterjee, P (Author) Other; Lam, HM (Author) Other; Santos, C (Author) Other; Coleman, IM (Author) Other; Ferreirinha, P (Author) Other; Manuel Vilanova (Author) ICBAS; da Cunha, NP (Author) Other; Carvalho, H (Author) Other; Moreira-Pais, A (Author) Other; Faustino-Rocha, A (Author) Other; Neto, T (Author) Other; da Costa, JB (Author) Other; Wright, JL (Author) Other; Ferreira, R (Author) Other; Oliveira, PA (Author) Other; Joaquim Mendes (Author) FEUP; Margarida Bastos (Author) FEUP; Colaco, B (Author) Other; Lopes, C (Author) Other; Black, PC (Author) Other; Sweeney, CJ (Author) Other; Nelson, PS (Author) Other

Journal

Title: Molecular Oncology

Vol. 17

Pages: 2709-2727

ISSN: 1574-7891

Publisher: Wiley-Blackwell

Indexing

ISI Web of Knowledge - 0 Citations

Scopus - 0 Citations

Other information

Authenticus ID: P-00Z-2S3

DOI: 10.1002/1878-0261.13504

Abstract (EN): 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-?B) is a major mechanism underlying chemoresistance, suggesting that its pharmacological inhibition may increase platinum efficacy. NF-?B signaling was investigated in two patient cohorts. The Cancer Genome Atlas (TCGA) was used to correlate NF-?B signaling and patient survival. The efficacy of cisplatin plus the NF-?B inhibitor dimethylaminoparthenolide (DMAPT) versus cisplatin or DMAPT alone was tested in vitro. Xenografted and immunocompetent MIBC mouse models were studied in vivo. Platinum-naive claudin-low MIBC showed constitutive NF-?B signaling and this was associated with reduced disease-specific survival in TCGA patients. Chemotherapy up-regulated NF-?B signaling and chemoresistance-associated genes, including SPHK1, PLAUR, and SERPINE1. 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-?B inhibition with platinum-based chemotherapy and conducting a clinical trial in MIBC patients.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 19