Histone deacetylase inhibitor BG45-mediated HO-1 expression induces apoptosis of multiple myeloma cells by the JAK2/STAT3 pathway
| Autor: | Jishi Wang, Sishi Tang, Xinyao Li, Weibing Wu, Bingqing Cheng, Dan Ma, Jibing Xu, Yongling Guo, Nana Zhe |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
STAT3 Transcription Factor
0301 basic medicine Cancer Research medicine.drug_class Apoptosis Cell Growth Processes Biology Resting Phase Cell Cycle 03 medical and health sciences Histone H3 0302 clinical medicine Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols medicine Humans Pharmacology (medical) Lenalidomide Multiple myeloma Pharmacology Histone deacetylase inhibitor G1 Phase Drug Synergism Janus Kinase 2 HDAC3 medicine.disease Thalidomide Histone Deacetylase Inhibitors Heme oxygenase 030104 developmental biology medicine.anatomical_structure Oncology Cell culture 030220 oncology & carcinogenesis Cancer research Bone marrow Multiple Myeloma Heme Oxygenase-1 Signal Transduction |
| Zdroj: | Anti-Cancer Drugs. 29:61-74 |
| ISSN: | 0959-4973 |
| DOI: | 10.1097/cad.0000000000000568 |
| Popis: | Multiple myeloma (MM) is a hematological malignancy that is characterized by the clonal expansion of plasma cells in the bone marrow. Histone deacetylases (HDACs) represent a new type of molecular targeted therapy for different types of cancers and promising targets for myeloma therapy. We showed that HDAC3 mRNA and protein levels of CD138 mononuclear cells from MM patients were higher than those in healthy donors. Therefore, we investigated the effects of a novel class I HDAC inhibitor BG45 on MM cells in vitro. BG45 downmodulated heme oxygenase 1 (HO-1) when class I HDACs decreased in MM cells. HO-1 is a target for the treatment of MM. Moreover, BG45 induced hyperacetylation of histone H3 and inhibited the growth, especially the apoptosis of MM cell lines. Treatment with BG45 induced apoptosis by downregulating bcl-2 and Bcl-xl, upregulating Bax and other antiapoptotic proteins and activating poly(ADP-ribose)polymerase, and decreasing protein levels of p-JAK2 and p-STAT3. These effects were partly blocked by HO-1. Correspondingly, BG45 led to an accumulation in the G0/G1 phase, accompanied by decreased levels of CDK4 and phospho-retinoblastoma protein, an increased level of p21, and a moderately reduced level of CDK2. Clinical use of single agents was limited because of toxic side effects and drug resistance. However, combining BG45 with lenalidomide exerted synergistic effects. In conclusion, we verified the potent antimyeloma activity of this novel HDAC inhibitor and that the combination of BG45 and lenalidomide is a new method for MM treatment. Thus, BG45 may be applicable to the treatment of MM and other hematological malignancies. |
| Databáze: | OpenAIRE |
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