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Tumor necrosis factor‑related apoptosis‑inducing ligand as a therapeutic option in urothelial cancer cells with acquired resistance against first‑line chemotherapy

Vallo, Stefan, Stege, Henner, Berg, Maximilian, Michaelis, Martin, Winkelmann, Ria, Rothweiler, Florian, Cinatl, Jindrich (2020) Tumor necrosis factor‑related apoptosis‑inducing ligand as a therapeutic option in urothelial cancer cells with acquired resistance against first‑line chemotherapy. Oncology Reports, 43 (4). pp. 1331-1337. ISSN 1021-335X. (doi:10.3892/or.2020.7487) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided) (KAR id:80270)

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Official URL:
https://doi.org/10.3892/or.2020.7487

Abstract

Patients with urothelial carcinoma frequently fail to respond to first‑line chemotherapy using cisplatin and gemcitabine due to development of resistant tumor cells. The aim of the present study was to investigate whether an alternative treatment with tumor necrosis factor‑related apoptosis‑inducing ligand (TRAIL) that induces tumor cell death via the extrinsic apoptotic pathway may be effective against chemotherapy‑resistant urothelial cancer cell lines. The viability of the urothelial cancer cell line RT112 and its chemotherapy‑adapted sublines was investigated by MTT assay. The expression of anti‑apoptotic proteins was determined by western blotting and the individual roles of cellular inhibitor of apoptosis protein (cIAP)1, cIAP2, x‑linked inhibitor of apoptosis protein (XIAP) and induced myeloid leukemia cell differentiation protein (Mcl‑1) were investigated by siRNA‑mediated depletion. In particular, the bladder cancer sublines that were resistant to gemcitabine and cisplatin were cross‑resistant to TRAIL. Resistant cells displayed upregulation of anti‑apoptotic molecules compared with the parental cell line. Treatment with the second mitochondrial activator of caspases (SMAC) mimetic LCL‑161 that antagonizes cIAP1, cIAP2 and XIAP resensitized chemoresistant cells to TRAIL. The resensitization of tumor cells to TRAIL was confirmed by depletion of antiapoptotic proteins with siRNA. Collectively, the findings of the present study demonstrated that SMAC mimetic LCL‑161 increased the sensitivity of the parental cell line RT112 and chemotherapy‑resistant sublines to TRAIL, suggesting that inhibiting anti‑apoptotic molecules renders TRAIL therapy highly effective for chemotherapy‑sensitive and ‑resistant urothelial cancer cells.

Item Type: Article
DOI/Identification number: 10.3892/or.2020.7487
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Divisions > Division of Natural Sciences > Biosciences
Depositing User: Martin Michaelis
Date Deposited: 26 Feb 2020 17:48 UTC
Last Modified: 04 Mar 2024 16:39 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/80270 (The current URI for this page, for reference purposes)

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