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.
Highlights
Neuroblastoma is the most common extracranial solid tumor in children [1,2,3]
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
Vincristine was identified as the Food and Drug Authority (FDA)-approved drug which exerted the best synergistic anticancer effects with JQ1 in vitro, and combination therapy with JQ1 and vincristine was highly effective in suppressing tumor progression in neuroblastoma-bearing mice
Summary
Neuroblastoma is the most common extracranial solid tumor in children [1,2,3]. MYCN gene amplification occurs in a quarter of primary neuroblastomas and is associated with N-Myc protein over-expression and poor patient survival [4,5,6]. JQ1 and I-BET151 are potent BET bromodomain inhibitors which interrupt the recruitment of BRD3 and BRD4 to chromatin to downregulate MYC, MYCN and BCL2 expression [12, 15,16,17,18,19,20,21]. Despite their promising therapeutic potential, BET bromodomain inhibitors do not cause tumor regression as single agents in vivo [12, 15,16,17,18, 20, 21]. Vincristine was identified as the Food and Drug Authority (FDA)-approved drug which exerted the best synergistic anticancer effects with JQ1 in vitro, and combination therapy with JQ1 and vincristine was highly effective in suppressing tumor progression in neuroblastoma-bearing mice
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