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

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.

Epigenome screening highlights that JMJD6 confers an epigenetic vulnerability and mediates sunitinib sensitivity in renal cell carcinoma

“…However, owing to publication space limits, the specific underlying resistance mechanisms induced by JMJD6 have not been thoroughly clarified. Given that JMJD6 regulating a relatively wide spectrum of targets such as BRD4, the toxicity and optimal doses of SKLB325 were warranted to evaluate based on in vitro and in vivo models 50,51 . Whether SKLB325 has an effect on a small fraction of JMJD6 low RCC samples to exhibit synergistic efficacy with sunitinib remains to be determined.…”

“…Given that JMJD6 regulating a relatively wide spectrum of targets such as BRD4, the toxicity and optimal doses of SKLB325 were warranted to evaluate based on in vitro and in vivo models. 50,51 Whether SKLB325 has an effect on a small fraction of JMJD6 low RCC samples to exhibit synergistic efficacy with sunitinib remains to be determined. In addition, although SKLB325 and sunitinib efficiently cooperate, the dosing quantity and order of these two drugs for optimized treatment will be of great importance to evaluate in mouse models.…”