EPZ-004777

Ectoparasites of rodents play significant roles in disease transmission to humans. Conventional poisoning potentially reduces the population densities of rodents, however, they may increase the ectoparasite loads on the surviving hosts. EP‐1 has been shown to have anti‐fertility effects on many rodent species, while ivermectin is effective in controlling ectoparasites. In this study, we examined the combined effects of EP‐1 and ivermectin mixture (iEP‐1) baits on rodents and their corresponding flea/tick loads.

In males, the weight of testis, epididymis, and seminiferous vesicle were reduced to less than 33%, 25%, and 17%, respectively, compared to the control group following administration of iEP‐1 for 7 days. The weight of the uterus increased by approximately 75%. After 5 days of iEP‐1 intake, all ticks were killed, whereas 94% of fleas on mice died after 3 days of bait intake. In the field test near Beijing, the flea index was reduced by more than 90% after 7 days of iEP‐1 bait delivery. In a field test in Inner Mongolia, the weights of testis, epididymis, and seminiferous vesicle were significantly reduced by 27%, 32%, and 57%, respectively, 2 weeks after iEP‐1 bait delivery. Approximately 36% rodents exhibited obvious uterine oedema accompanied by a weight increase of about 150%. The flea index was reduced by over 90%.

Our results indicated that iEP‐1 is a promising treatment for reducing the abundance of both small rodents and their ectoparasites; this will be effective for managing rodent damage and transmission of rodent‐borne diseases associated with fleas and ticks. © 2022 Society of Chemical Industry.

DOT1L, a specific H3K79 methyltransferase, has a tumour‐promoting role in various cancers, including triple‐negative breast cancer (TNBC). However, the molecular mechanism by which the deregulated DOT1L promotes cancer progression is unclear. Herein, we show that a significantly higher basal level of DOTL1 strongly correlates with MTDH, an oncogene, in clinical TNBC patient cohorts and mediates TNBC progression by enhancing MTDH‐induced angiogenesis. In parallel, severe combined immunodeficiency mice‐bearing MDA‐MB‐231 cells with MTDH‐Wt or MTDHΔ7 (spliced isoform of MTDH) overexpression constructs showed enhanced blood vessel formations at the tumour site in comparison with control groups. Selective inhibition of DOT1L by EPZ004777, a specific DOT1L inhibitor, or siDOT1L, significantly impaired MTDH‐induced proliferation, invasion and angiogenic markers expression in TNBC cells. ChIP assay revealed that Dot1L promotes MTDH‐Wt/Δ7 transcription by increasing H3K79me3 levels on its promoter. Dot1L depletion reversed this effect. Mechanistically, DOT1L‐induced MTDH caused enhanced nuclear factor kappa B (NF‐κB) occupancy on the hypoxia‐inducible factor1α (HIF1α) promoter and increased its transcription, leading to elevated levels of proangiogenic mediators in TNBC cells. Moreover, the condition media obtained from MDA‐MB‐231 cells stably expressing either MTDH‐Wt or MTDHΔ7 treated with EPZ004777 or Bay‐11‐7082 (NF‐κB inhibitor) or FM19G11 (HIF1α inhibitor) significantly inhibited MTDH‐induced tube formation in human umbilical vein endothelial cells, rat aortic ring sprouting and vessel formations by chick chorioallantoic membrane assay mimicking physiological angiogenic vasculature. Collectively, our findings reveal a novel epigenetic regulation of MTDH by DOTL1, which drives angiogenesis, and that the therapeutic disruption of the DOT1L‐MTDH‐NF‐κB‐HIF1α axis may have usefulness in the management of TNBC.