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
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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