The γ-secretase inhibitor GSI-I interacts synergistically with the proteasome inhibitor bortezomib to induce ALK+ anaplastic large cell lymphoma cell apoptosis
| Autor: | Qingxiu Dang, Yaping Zhang, Lili Chen, Wenyu Shi, Hong Zhou, Mengqi Xu, Xuefen You |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Antineoplastic Agents Apoptosis Mice SCID Bortezomib Mice 03 medical and health sciences 0302 clinical medicine In vivo Cell Line Tumor hemic and lymphatic diseases medicine Animals Humans Molecular Targeted Therapy Protein kinase B Anaplastic large-cell lymphoma Chemistry Kinase Drug Synergism Cell Biology medicine.disease 030104 developmental biology Proteasome 030220 oncology & carcinogenesis Proteasome inhibitor Cancer research Lymphoma Large-Cell Anaplastic Female Amyloid Precursor Protein Secretases Proteasome Inhibitors medicine.drug |
| Zdroj: | Cellular Signalling. 59:76-84 |
| ISSN: | 0898-6568 |
| DOI: | 10.1016/j.cellsig.2019.03.013 |
| Popis: | Single agent treatment of the γ-secretase inhibitor (GSI-I) or proteasome inhibitor in anaplastic lymphoma kinase positive anaplastic large cell lymphoma (ALK+ ALCL) shows limited response and considerable toxicity. Here, we examined the effects of the combination of low dose GSI-I and the proteasome inhibitor bortezomib (BTZ) in ALK+ ALCL cells in vivo and in vitro. We found that ALK+ ALCL cells treated with the BTZ and GSI-I combination treatment showed elevated apoptosis, consistent with increased caspase activation, compared with BTZ or GSI-I alone. The combination treatment also inhibited AKT and extracellular signal-related kinase pathways, as well as stress-related cascades, including the c-jun N-terminal kinase and stress-activated kinases. Moreover, combined treatment in a murine xenograft model resulted in increased apoptosis in tumor tissues and reduced tumor growth. Our results reveal the synergistic anti-tumor effects of low dose inhibitors against γ-secretase and the proteasome and suggest the potential application of the tolerable BTZ/GSI-I combined agents in treating ALK+ ALCL in future clinical treatment. |
| Databáze: | OpenAIRE |
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