Low-Dose Triptolide Enhances Bromodomain Inhibitor JQ1-Induced Apoptosis of Acute Myeloid Leukemia Cells Via Down-Regulation of c-Myc Following RAS/MEK/ERK Inhibition

The current therapy for acute myeloid leukemia (AML) remains greatly challengeable because most patients ultimately relapse due to resistant to current chemotherapies. Therefore, development of novel therapies using a variety of agents targeting varying pathways is needed to further improve patients' survival. Here we report that low dose triptolide (TPL), a natural product derived from plant Tripterygium wilfordii, could enhance bromodomain inhibitor JQ1-induced apoptosis of AML cell lines as well as primary cells from patients with de novo and relapsed or refractory (R/R) AML, while sparing their normal counterparts. Moreover, combination of TPL and JQ1 showed a more powerful activity to suppress AML cell growth in a xenograft model than single agent. Mechanistically, the synergetic effects of TPL and JQ1 were associated with impaired mitochondrial membrane potential, increased reactive oxygen species (ROS) production and imbalance of the Bcl2 family of pro-apoptotic and anti-apoptotic proteins, leading to caspase-dependent apoptosis. Meanwhile, RNAseq analysis revealed that ERK/MAPK signaling cascades are responsible for the enhanced activity of TPL in combination with JQ1 against AML. In summary, this study demonstrates that low-dose TPL synergizes with JQ1 to target AML through inhibiting ERK/MAPK signaling and mitochondrial apoptosis pathway, supporting a potential option of combination of TPL and JQ1 for AML treatment.