Low-dose triptolide enhances antitumor effect of JQ1 on acute myeloid leukemia through inhibiting RNA polymerase II in vitro and in vivo

Yuanfei Shi, Haijun Zhao, Jing Ye, Zhifeng Li, Manman Deng, Jie Zha, Yong Zhou, Hanyan Zeng, Yun Lin, Xuan Pu, Chengcen Guo, Haihan Song, Yi Qiu, Bing Xu

Research output: Contribution to journalArticlepeer-review

2 Citations (SciVal)

Abstract

The bromodomain and extra-terminal (BET) domain inhibitor JQ1 exerts potent anticancer activity in various cancer cells. However, the resistance to BET inhibitors in leukemia stem cells limits its implication in acute myeloid leukemia (AML). High concentration of triptolide (TPL) presents anticancer activities but with adverse effects. Here, we investigated whether the combination of low-dose TPL with JQ1 could help to circumvent the dilemma of drug resistance and side effect in treating AML. AML cell lines, primary cells from 10 AML patients with different status, as well as AML mice model were subjected to different treatments and apoptotic related protein expression were evaluated. Data showed that low-dose TPL combined with JQ1 effectively killed AML cell lines and primary cells from AML patients without exerting significantly greater lethal activity against normal cells. Mechanism study revealed that low-dose TPL combined with JQ1 triggered reactive oxygen species production and induced mitochondrial-mediated apoptosis in AML cells, in which the inhibition of RNA polymerase II to downregulate c-Myc was mainly responsible for the enhanced activity of TPL in combination with JQ1. In vivo study presented that cotreatment with low-dose TPL and JQ1 significantly reduced tumor burden of the NOD/SCID mice engrafted with MOLM-13 cells. In conclusion, low-dose TPL enhanced the antitumor effect of JQ1 on AML without increasing the side effects, supporting a potential option for AML treatment.

Original languageEnglish (US)
Pages (from-to)1076-1087
Number of pages12
JournalMolecular Carcinogenesis
Volume59
Issue number9
DOIs
StatePublished - Sep 1 2020

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cancer Research

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