Activation of unfolded protein response overcomes Ibrutinib resistance in diffuse large B-cell lymphoma
Autor: | Yubo Zhou, Zhi-jia Wang, Yu-qi Xiang, Hu Xiaobei, Tiancheng Dong, Wen-Biao Wu, Lei Xu, Kan Weijuan, Jia Li, Hanlin Wang, Bo Feng, Jia-Nan Li, Anhui Gao, Xiaotuan Zhang, Chunmei Xia |
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Rok vydání: | 2020 |
Předmět: |
X-Box Binding Protein 1
0301 basic medicine Antineoplastic Agents Apoptosis Mice SCID Deoxyglucose Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Piperidines Mice Inbred NOD immune system diseases Cell Line Tumor hemic and lymphatic diseases medicine Animals Humans Bruton's tyrosine kinase Pharmacology (medical) Cell Proliferation Pharmacology biology Chemistry Cell growth Adenine Drug Synergism General Medicine medicine.disease Xenograft Model Antitumor Assays Lymphoma Gene Expression Regulation Neoplastic 030104 developmental biology Drug Resistance Neoplasm Cell culture 030220 oncology & carcinogenesis Ibrutinib Unfolded Protein Response biology.protein Cancer research Female Lymphoma Large B-Cell Diffuse Diffuse large B-cell lymphoma Tyrosine kinase |
Zdroj: | Acta Pharmacol Sin |
ISSN: | 1745-7254 1671-4083 |
Popis: | 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. |
Databáze: | OpenAIRE |
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