Doramectin: Uses; Side effect; Anti-cancer effects

Uses of Doramectin

Doramectin is a traditional anthelmintic veterinary drug that has been used to treat helminthic infections, not only to relieve clinical signs but also to cure oesophageal nodules, and is the drug of choice in many endemic countries. It can also be used to treat systemic helminthic mites in dogs and is used mainly in pigs, cattle, deer, dog, cat and sheep. The plasma disposition of doramectin after subcutaneous or oral administration is similar to that of ivermectin. It is excreted from the faeces mainly as a non-metabolised drug.

Side Effect

Ten lions (Panthera leo) that were treated with a single injection of doramectin at a dose ranging between 0.2 mg/kg and 0.5 mg/kg showed clinical signs consistent with avermectin toxicity, namely ataxia, hallucinations, and mydriasis. Two subsequently died whereas the other eight lions recovered after 4-5 days with symptomatic therapy. Post-mortem examinations of the two that died showed cyanosis, severe pulmonary oedema, pleural effusion, and pericardial effusion, with histopathology not revealing any abnormalities. In both these lions, doramectin brain and liver tissue concentrations were elevated. Although doramectin is regularly used in wild felids, to date there have been no reports of avermectin toxicity in the literature.

Anti-cancer effects

Doramectin (DRM) is a kind of avermectin drugs, and it has been shown that DRM has anti-cancer effects. However, the molecular mechanism of DRM in programmed cell death (PCD) aspects is still unclear. The objective of this study was to confirm whether DRM induced PCD in glioma cells. In this experiment, the MTT assay and Ki-67 assay were used to detect in vitro cell viability and in vivo tumor proliferation. Then, the effect of DRM on PCD was analyzed by transcriptome comparison. Next, Endogenous apoptosis was detected by transmission electron microscopy (TEM), the DNA gel electrophoresis, JC-1 assay, western blotting and qRT-PCR. Meanwhile, necroptosis was detected by TEM, Hoechst 33342, FITC and PI staining assay, western blotting. We found DRM induced apoptosis through Bcl-2/Bax/Caspase-3 pathway. And, DRM induced ROS overproduction, then ROS caused necroptosis through RIPK1/RIPK3/MLKL pathway, Mitochondria acted as a bridge between the two pathways. Our research provided new insight with the function of anti-cancer of DRM. These results demonstrated DRM may be used as potential therapeutic agents inducing apoptosis and necroptosis for cancer therapy.

References:

[1] DU S, LIANG H, ZHOU L, et al. Effect of doramectin on programmed cell death pathway in glioma cells[J]. Clinical and Translational Oncology, 2023: 1-13. DOI:10.1007/s12094-023-03147-z.

[2] MARÍA DEL MAR GIL-DÍAZ*. Potential Diffusion of Doramectin into a Soil Amended with Female Pig Manure. A Field Experiment[J]. Journal of Agricultural and Food Chemistry, 2011, 59 19: 10635-10640. DOI:10.1021/jf2020655.