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

ABSTRACT: 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 in vitro. Xenografted and immunocompetent MIBC mouse models were studied in vivo. 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 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-κB inhibition with platinum-based chemotherapy and conducting a clinical trial in MIBC patients.

SUBMITTER: Gil da Costa RM

PROVIDER: S-EPMC10701775 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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

Gil da Costa Rui M RM Levesque Christine C Bianchi-Frias Daniella D Chatterjee Payel P Lam Hung-Ming HM Santos Carlos C Coleman Ilsa M IM Ferreirinha Pedro P Vilanova Manuel M Pinto da Cunha Nazaré N Carvalho Hugo H Moreira-Pais Alexandra A Faustino-Rocha Ana A Neto Tiago T Batista da Costa José J Wright Jonathan L JL Ferreira Rita R Oliveira Paula A PA Mendes Joaquim J Bastos Margarida M S M MMSM Colaço Bruno B Lopes Carlos C Black Peter C PC Sweeney Christopher J CJ Nelson Peter S PS

Molecular oncology 20230920 12

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 ...[more]

PMID: 37533407

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Project description:The high activation of protein kinase B (AKT)/nuclear factor‑κB (NF‑κB) signaling has often been associated with the induction of non‑small cell lung cancer (NSCLC) cell survival and resistance to cisplatin, which is one of the most widely used chemotherapeutic drugs in the treatment of NSCLC. The inhibition of AKT/NF‑κB can potentially be used as a molecular target for cancer therapy. Eurycomalactone (ECL), a quassinoid from Eurycoma longifolia Jack, has previously been revealed to exhibit strong cytotoxic activity against the human NSCLC A549 cell line, and can inhibit NF‑κB activity in TNF‑α‑activated 293 cells stably transfected with an NF‑κB luciferase reporter. The present study was the first to investigate whether ECL inhibits the activation of AKT/NF‑κB signaling, induces apoptosis and enhances chemosensitivity to cisplatin in human NSCLC cells. The anticancer activity of ECL was evaluated in two NSCLC cell lines, A549 and Calu‑1. ECL decreased the viability and colony formation ability of both cell lines by inducing cell cycle arrest and apoptosis through the activation of pro‑apoptotic caspase‑3 and poly (ADP‑ribose) polymerase, as well as the reduction of anti‑apoptotic proteins Bcl‑xL and survivin. In addition, ECL treatment suppressed the levels of AKT (phospho Ser473) and NF‑κB (phospho Ser536). Notably, ECL significantly enhanced cisplatin sensitivity in both assessed NSCLC cell lines. The combination treatment of cisplatin and ECL promoted cell apoptosis more effectively than cisplatin alone, as revealed by the increased cleaved caspase‑3, but decreased Bcl‑xL and survivin levels. Exposure to cisplatin alone induced the levels of phosphorylated‑AKT and phosphorylated‑NF‑κB, whereas co‑treatment with ECL inhibited the cisplatin‑induced phosphorylation of AKT and NF‑κB, leading to an increased sensitization effect on cisplatin‑induced apoptosis. In conclusion, ECL exhibited an anticancer effect and sensitized NSCLC cells to cisplatin through the inactivation of AKT/NF‑κB signaling. This finding provides a rationale for the combined use of chemotherapy drugs with ECL to improve their efficacy in NSCLC treatment.

Dataset Information

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

Publications

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

Similar Datasets

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