Antimyeloma activity of bromodomain inhibitors on the human myeloma cell line U266 by downregulation of MYCL.
Bromodomain and extraterminal protein (BET) inhibitors suppress the expression of c-MYC. U266, a human myeloma cell line, expresses the MYCL gene, but not the c-MYC gene. Our aim was to analyse the antimyeloma activity of BET inhibitors on U266 cells. Two BET inhibitors, I-BET151 and JQ1, were tested. U266 cell proliferation decreased to 61.5 and 54.0% of the control after incubation with 500 nmol/l I-BET151 for 72 and 96 h and to 53.5 and 56.4% of control after incubation with 500 nmol/l JQ1 for 72 and 96 h by MTS tetrazolium, respectively. BET inhibitors induced cell cycle arrest at the G1 phase in U266 cells, but did not induce apoptosis by flow cytometry. According to Gene Set Enrichment Analysis, MYC-related genes were significantly downregulated in U266 cells treated with I-BET151 similar to KMS11 cells that expressed c-MYC. The MYCL1 was expressed in U266 cells, whereas c-MYC and MYCN were not by quantitative real-time reverse-transcription-PCR. Incubation with I-BET151 induced downregulation of MYCL1 in U266 cells. BET inhibitors decreased the cell proliferation in U266 cells with overexpression of MYCL less than those without overexpression of MYCL. BET inhibitors induce G1 arrest without apoptosis and interfere with the proliferation of U266 myeloma cells, which express MYCL, but not c-MYC. BET inhibitors might be active in cancers that express MYCL, but not c-MYC.
aDepartment of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University bDepartment of Internal Medicine, Division of Clinical Oncology/Hematology cCore Research Facilities for Basic Science, Division of Molecular Genetics, Jikei University School of Medicine, Tokyo, Japan.
Kazuhito
K
Suzuki
Kouhei
K
Yamamoto
Yasuhiro
Y
Arakawa
Hisashi
H
Yamada
Keisuke
K
Aiba
Masanobu
M
Kitagawa
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000071447:N-Myc Proto-Oncogene Protein / Q000378:metabolism; D000072417:Protein Domains; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology*
C561695:(+)-JQ1 compound; D000970:Antineoplastic Agents; D001381:Azepines; C568713:GSK1210151A; D006576:Heterocyclic Compounds, 4 or More Rings; C000596782:MYCL protein, human; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D016271:Proto-Oncogene Proteins c-myc; D014230:Triazoles