The BET bromodomain inhibitor exerts the most potent synergistic anticancer effects with quinone-containing compounds and anti-microtubule drugs

// Pei Y. Liu 1, * , Nicholas Sokolowski 1, * , Su T. Guo 2, * , Faraz Siddiqi 1 , Bernard Atmadibrata 1 , Thomas J. Telfer 3 , Yuting Sun 1 , Lihong Zhang 1, 4 , Denise Yu 1 , Joshua Mccarroll 1 , Bing Liu 1 , Rui H. Yang 5 , Xiang Y. Guo 5 , Andrew E. Tee 1 , Ken Itoh 6 , Jenny Wang 1, 7 , Maria Kavallaris 1 , Michelle Haber 1 , Murray D. Norris 1, 7 , Belamy B. Cheung 1 , Jennifer A. Byrne 8 , David S. Ziegler 1, 9 , Glenn M. Marshall 1, 9 , Marcel E. Dinger 10, 11 , Rachel Codd 3 , Xu D. Zhang 2, 5 , Tao Liu 1, 7 1 Children’s Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, Australia 2 School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia 3 School of Medical Sciences (Pharmacology) and Bosch Institute, The University of Sydney, Sydney, Australia 4 Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, China 5 Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Affiliated Hospital of Shanxi Medical University, Shanxi, China 6 Department of Stress Response Science, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, Hirosaki, Japan 7 Centre for Childhood Cancer Research, University of New South Wales Medicine, University of New South Wales Australia, Sydney, Australia 8 Children’s Cancer Research Unit, Kids Research Institute, The Children’s Hospital at Westmead, Westmead, Australia 9 Kids Cancer Centre, Sydney Children’s Hospital, High Street, Randwick, Australia 10 Garvan Institute of Medical Research, Darlinghurst, Australia 11 St Vincent’s Clinical School, University of New South Wales Medicine, University of New South Wales Australia, Darlinghurst, Australia * These authors have contributed equally to this work Correspondence to: Tao Liu, email: tliu@ccia.unsw.edu.au Keywords: JQ1, neuroblastoma, quinone-containing compounds, vincristine, nanaomycin Received: June 06, 2016     Accepted: September 28, 2016     Published: October 13, 2016 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 G 2 /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.