Acta pharmacologica Sinica, 2021-05, Vol.42 (5), p.814-823
2021
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- Autor(en) / Beteiligte
- Titel
- Activation of unfolded protein response overcomes Ibrutinib resistance in diffuse large B-cell lymphoma
- Ist Teil von
- Acta pharmacologica Sinica, 2021-05, Vol.42 (5), p.814-823
- Ort / Verlag
- Singapore: Springer Singapore
- Erscheinungsjahr
- 2021
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Diffuse large B-cell lymphoma (DLBCL) is the most widespread type of non-Hodgkin lymphoma (NHL). As the most aggressive form of the DLBCL, the activated B-cell-like (ABC) subtype is often resistant to standard chemotherapies. Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib provides a potential therapeutic approach for the DLBCL but fails to improve the outcome in the phase III trial. In the current study, we investigated the molecular mechanisms underlying ibrutinib resistance and explored new combination therapy with ibrutinib. We generated an ibrutinib-resistant ABC-DLBCL cell line (OCI-ly10-IR) through continuous exposure to ibrutinib. Transcriptome analysis of the parental and ibrutinib-resistant cell lines revealed that the ibrutinib-resistant cells had significantly lower expression of the unfolded protein response (UPR) marker genes. Overexpression of one UPR branch-XBP1s greatly potentiated ibrutinib-induced apoptosis in both sensitive and resistant cells. The UPR inhibitor tauroursodeoxycholic acid (TUDCA) partially reduced the apoptotic rate induced by the ibrutinib in sensitive cells. The UPR activator 2-deoxy- D -glucose (2-DG) in combination with the ibrutinib triggered even greater cell growth inhibition, apoptosis, and stronger calcium (Ca 2+ ) flux inhibition than either of the agents alone. A combination treatment of ibrutinib (15 mg·kg −1 ·d −1 , po.) and 2-DG (500 mg/kg, po, b.i.d.) synergistically retarded tumor growth in NOD/SCID mice bearing OCI-ly10-IR xenograft. In addition, ibrutinib induced the UPR in the sensitive cell lines but not in the resistant cell lines of the DLBCL. There was also a combined synergistic effect in the primary resistant DLBCL cell lines. Overall, our results suggest that targeting the UPR could be a potential combination strategy to overcome ibrutinib resistance in the DLBCL.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1671-4083eISSN: 1745-7254DOI: 10.1038/s41401-020-00505-3Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8115113
- Format
- –
- Schlagworte
- Adenine - analogs & derivatives, Adenine - therapeutic use, Animals, Antineoplastic Agents - therapeutic use, Apoptosis, Apoptosis - drug effects, B-cell lymphoma, Biomedical and Life Sciences, Biomedicine, Bruton's tyrosine kinase, Calcium, Cell Line, Tumor, Cell Proliferation - drug effects, Deoxyglucose - therapeutic use, Drug Resistance, Neoplasm - drug effects, Drug Resistance, Neoplasm - physiology, Drug Synergism, Enzyme inhibitors, Female, Gene expression, Gene Expression Regulation, Neoplastic - drug effects, Glucose, Growth inhibition, Humans, Immunology, Internal Medicine, Lymphocytes B, Lymphoma, Lymphoma, Large B-Cell, Diffuse - drug therapy, Lymphoma, Large B-Cell, Diffuse - genetics, Lymphoma, Large B-Cell, Diffuse - physiopathology, Medical Microbiology, Mice, Mice, Inbred NOD, Mice, SCID, Molecular modelling, Non-Hodgkin's lymphoma, Pharmacology/Toxicology, Piperidines - therapeutic use, Protein folding, Protein-tyrosine kinase, Targeted cancer therapy, Tauroursodeoxycholic acid, Transcriptomes, Unfolded Protein Response - drug effects, Unfolded Protein Response - physiology, Vaccine, X-Box Binding Protein 1 - genetics, X-Box Binding Protein 1 - metabolism, Xenograft Model Antitumor Assays, Xenografts