The BET bromodomain inhibitor exerts the most potent synergistic anticancer effects with quinone-containing compounds and anti-microtubule drugs
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Pei Y. Liu1,*, Nicholas Sokolowski1,*, Su T. Guo2,*, Faraz Siddiqi1, Bernard Atmadibrata1, Thomas J. Telfer3, Yuting Sun1, Lihong Zhang1,4, Denise Yu1, Joshua Mccarroll1, Bing Liu1, Rui H. Yang5, Xiang Y. Guo5, Andrew E. Tee1, Ken Itoh6, Jenny Wang1,7, Maria Kavallaris1, Michelle Haber1, Murray D. Norris1,7, Belamy B. Cheung1, Jennifer A. Byrne8, David S. Ziegler1,9, Glenn M. Marshall1,9, Marcel E. Dinger10,11, Rachel Codd3, Xu D. Zhang2,5, Tao Liu1,7
1Children’s Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, Australia
2School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia
3School of Medical Sciences (Pharmacology) and Bosch Institute, The University of Sydney, Sydney, Australia
4Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, China
5Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Affiliated Hospital of Shanxi Medical University, Shanxi, China
6Department of Stress Response Science, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
7Centre for Childhood Cancer Research, University of New South Wales Medicine, University of New South Wales Australia, Sydney, Australia
8Children’s Cancer Research Unit, Kids Research Institute, The Children’s Hospital at Westmead, Westmead, Australia
9Kids Cancer Centre, Sydney Children’s Hospital, High Street, Randwick, Australia
10Garvan Institute of Medical Research, Darlinghurst, Australia
11St 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
Tao Liu, email: email@example.com
Keywords: JQ1, neuroblastoma, quinone-containing compounds, vincristine, nanaomycin
Received: June 06, 2016 Accepted: September 28, 2016 Published: October 13, 2016
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.
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