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,it has a variety of biological activities and its root is the main part of its biological function.It's been reported that the killing of tumor cells by BET inhibitor through p38MAPK and c-Myc signals.Moreover,triptolide can effectively enhance its killing effect on cancer cells,so it can be inferred that p38 MAPK and c-myc related signaling pathway play an important role in inhibiting tumor cell growth.It 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.