title: The BET bromodomain inhibitor exerts the most potent synergistic anticancer effects with quinone-containing compounds and anti-microtubule drugs.
abstract: BET bromodomain inhibitors are very promising novel anticancer agents, however, single therapy does not cause tumor regression in mice, suggesting the need for combination therapy. After screening a library of 2697 small molecule compounds, we found that two classes of compounds, the quinone-containing compounds such as nanaomycin and anti-microtubule drugs such as vincristine, exerted the best synergistic anticancer effects with the BET bromodomain inhibitor JQ1 in neuroblastoma cells. Mechanistically, the quinone-containing compound nanaomycin induced neuroblastoma cell death but also activated the Nrf2-antioxidant signaling pathway, and the BET bromodomain proteins BRD3 and BRD4 formed a protein complex with Nrf2. Treatment with JQ1 blocked the recruitment of Nrf2 to the antioxidant responsive elements at Nrf2 target gene promoters, and JQ1 exerted synergistic anticancer effects with nanaomycin by blocking the Nrf2-antioxidant signaling pathway. JQ1 and vincristine synergistically induced neuroblastoma cell cycle arrest at the G2/M phase, aberrant mitotic spindle assembly formation and apoptosis, but showed no effect on cell survival in normal non-malignant cells. Importantly, co-treatment with JQ1 and vincristine synergistically suppressed tumor progression in neuroblastoma-bearing mice. These results strongly suggest that patients treated with BET bromodomain inhibitors in clinical trials should be co-treated with vincristine.
authors.affiliation: Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, Australia.
authors.forename: Pei Y
authors.initials: PY
authors.lastname: Liu
authors.affiliation: Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, Australia.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Sokolowski
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.
authors.forename: Su T
authors.initials: ST
authors.lastname: Guo
authors.affiliation: Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, Australia.
authors.forename: Faraz
authors.initials: F
authors.lastname: Siddiqi
authors.affiliation: Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, Australia.
authors.forename: Bernard
authors.initials: B
authors.lastname: Atmadibrata
authors.affiliation: School of Medical Sciences (Pharmacology) and Bosch Institute, The University of Sydney, Sydney, Australia.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Telfer
authors.affiliation: Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, Australia.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, Australia.|Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: Lihong
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, Australia.
authors.forename: Denise
authors.initials: D
authors.lastname: Yu
authors.affiliation: Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, Australia.
authors.forename: Joshua
authors.initials: J
authors.lastname: Mccarroll
authors.affiliation: Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, Australia.
authors.forename: Bing
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Affiliated Hospital of Shanxi Medical University, Shanxi, China.
authors.forename: Rui H
authors.initials: RH
authors.lastname: Yang
authors.affiliation: Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Affiliated Hospital of Shanxi Medical University, Shanxi, China.
authors.forename: Xiang Y
authors.initials: XY
authors.lastname: Guo
authors.affiliation: Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, Australia.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Tee
authors.affiliation: Department of Stress Response Science, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Itoh
authors.affiliation: Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, Australia.|Centre for Childhood Cancer Research, University of New South Wales Medicine, University of New South Wales Australia, Sydney, Australia.
authors.forename: Jenny
authors.initials: J
authors.lastname: Wang
authors.affiliation: Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, Australia.
authors.forename: Maria
authors.initials: M
authors.lastname: Kavallaris
authors.affiliation: Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, Australia.
authors.forename: Michelle
authors.initials: M
authors.lastname: Haber
authors.affiliation: Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, Australia.|Centre for Childhood Cancer Research, University of New South Wales Medicine, University of New South Wales Australia, Sydney, Australia.
authors.forename: Murray D
authors.initials: MD
authors.lastname: Norris
authors.affiliation: Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, Australia.
authors.forename: Belamy B
authors.initials: BB
authors.lastname: Cheung
authors.affiliation: Children's Cancer Research Unit, Kids Research Institute, The Children's Hospital at Westmead, Westmead, Australia.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Byrne
authors.affiliation: Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, Australia.|Kids Cancer Centre, Sydney Children's Hospital, High Street, Randwick, Australia.
authors.forename: David S
authors.initials: DS
authors.lastname: Ziegler
authors.affiliation: Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, Australia.|Kids Cancer Centre, Sydney Children's Hospital, High Street, Randwick, Australia.
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Marshall
authors.affiliation: Garvan Institute of Medical Research, Darlinghurst, Australia.|St Vincent's Clinical School, University of New South Wales Medicine, University of New South Wales Australia, Darlinghurst, Australia.
authors.forename: Marcel E
authors.initials: ME
authors.lastname: Dinger
authors.affiliation: School of Medical Sciences (Pharmacology) and Bosch Institute, The University of Sydney, Sydney, Australia.
authors.forename: Rachel
authors.initials: R
authors.lastname: Codd
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.|Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Affiliated Hospital of Shanxi Medical University, Shanxi, China.
authors.forename: Xu D
authors.initials: XD
authors.lastname: Zhang
authors.affiliation: Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, Australia.|Centre for Childhood Cancer Research, University of New South Wales Medicine, University of New South Wales Australia, Sydney, Australia.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001381:Azepines / Q000008:administration & dosage / Q000494:pharmacology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009285:Naphthoquinones / Q000008:administration & dosage* / Q000494:pharmacology; D009447:Neuroblastoma / Q000188:drug therapy*; D009687:Nuclear Proteins / Q000378:metabolism; D000072417:Protein Domains / Q000187:drug effects; D016601:RNA-Binding Proteins / Q000378:metabolism; D054852:Small Molecule Libraries / Q000008:administration & dosage / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology; D050257:Tubulin Modulators / Q000008:administration & dosage* / Q000494:pharmacology; D014750:Vincristine / Q000008:administration & dosage / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; D018797:Cell Cycle Proteins; D051267:NF-E2-Related Factor 2; D009285:Naphthoquinones; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D054852:Small Molecule Libraries; D014157:Transcription Factors; D014230:Triazoles; D050257:Tubulin Modulators; D014750:Vincristine; C561695:(+)-JQ1 compound; C109106:BRD3 protein, human; D000092468:Bromodomain Containing Proteins; C441289:BRD4 protein, human; C495635:NFE2L2 protein, human
keywords: JQ1; nanaomycin; neuroblastoma; quinone-containing compounds; vincristine