Doxycycline hyclate

Doxycycline hyclate is a derivative of tetracycline and possesses the activities of anti-inflammatory and antimicrobial. Doxycycline hyclate is an orally active and broad-spectrum metalloproteinase (MMP) inhibitor^[5].Doxycycline hyclate treatment reduces MMP-8 and -9 levels and inhibits expression of tissue MMP-2 and MMP-9. Moreover, treatment with doxycycline hyclate significantly reduces the incidence of intracranial aneurysms. Doxycycline hyclate has also been reported to be an anti-inflammatory agent based on its inhibition of matrix metalloproteinases. In addition, doxycycline has potent antimalarial activity with IC₅₀ value of 320nM at 96h in vitro^{[2 3]}.

Doxycycline hyclate inhibits dengue virus replication in vitro with a temperature-dependent manner. The IC₅₀ value is 52.3μM at 37°C and 26.7μM at 40°C. It inhibits the dengue virus via inhibiting the NS2B-NS3 serine protease of the virus^[5]

The ability of doxycycline hyclate to cause severe mitonuclear protein imbalance in glioma and astroglial cells, especially at high concentrations. Doxycycline hyclate had no effect on cell growth at concentrations regularly used to induce gene expression. Only the highest tested concentration of doxycycline hyclate (10 ug/mL) impaired cell growth^[4].In human cell lines, commonly used concentrations of doxycycline hyclate change gene expression patterns and concomitantly shift metabolism towards a more glycolytic phenotype, evidenced by increased lactate secretion and reduced oxygen consumption[7].Doxycyline can inhibit the viability and proliferation of breast cancer cells and BCSCs, decrease mammosphere forming efficiency, migration and invasion, and EMT of breast cancer cells. Expression of stem cell factors were also significantly downregulated after doxycycline hyclate treatment^[8]

In mouse model of P. berghei malaria, Doxycycline hyclate exhibited potent antimalarial activity at 50 mg/kg and activity was suboptimal at 10 mg/kg ^[1].Doxycycline hyclate treatment inhibits the activity of tissue MMP and attenuates the decrease in the collagen content in aortas of mice haploinsufficient for collagen III, as well as prevents the development of stress-induced vessel pathology. The results suggest that doxycycline hyclate merits clinical testing as a treatment for vEDS(The vascular form of Ehlers-Danlos syndrome)^[6]

References:
[1]: Rothan HA, Mohamed Z, et,al.Inhibitory effect of doxycycline against dengue virus replication in vitro. Arch Virol. 2014 Apr;159(4):711-8. doi: 10.1007/s00705-013-1880-7. Epub 2013 Oct 19. PMID: 24142271.
[2]:Maradni A, Khoshnevisan A, et,al. Role of matrix metalloproteinases (MMPs) and MMP inhibitors on intracranial aneurysms: a review article. Med J Islam Repub Iran. 2013 Nov;27(4):249-54. PMID: 24926188; PMCID: PMC4011417.
[3]:Draper MP, Bhatia B, et,al. In vitro and in vivo antimalarial efficacies of optimized tetracyclines. Antimicrob Agents Chemother. 2013 Jul;57(7):3131-6. doi: 10.1128/AAC.00451-13. Epub 2013 Apr 29. PMID: 23629719; PMCID: PMC3697387.
[4]: Luger AL, Sauer B, et,al. Doxycycline Impairs Mitochondrial Function and Protects Human Glioma Cells from Hypoxia-Induced Cell Death: Implications of Using Tet-Inducible Systems. Int J Mol Sci. 2018 May 17;19(5):1504. doi: 10.3390/ijms19051504. PMID: 29772845; PMCID: PMC5983704.
[5]: Manchado E, Weissmueller S, et,al. A combinatorial strategy for treating KRAS-mutant lung cancer. Nature. 2016 Jun 30;534(7609):647-51. doi: 10.1038/nature18600. Epub 2016 Jun 22. PMID: 27338794; PMCID: PMC4939262.
[6]: Briest W, Cooper TK, et,al. Doxycycline ameliorates the susceptibility to aortic lesions in a mouse model for the vascular type of Ehlers-Danlos syndrome. J Pharmacol Exp Ther. 2011 Jun;337(3):621-7. doi: 10.1124/jpet.110.177782. Epub 2011 Mar 1. PMID: 21363928; PMCID: PMC3101011.
[7]: Ahler E, Sullivan WJ, et,al. Doxycycline alters metabolism and proliferation of human cell lines. PLoS One. 2013 May 31;8(5):e64561. doi: 10.1371/journal.pone.0064561. PMID: 23741339; PMCID: PMC3669316.
[8]: Zhang L, Xu L, et,al. Doxycycline inhibits the cancer stem cell phenotype and epithelial-to-mesenchymal transition in breast cancer. Cell Cycle. 2017 Apr 18;16(8):737-745. doi: 10.1080/15384101.2016.1241929. Epub 2016 Oct 18. PMID: 27753527; PMCID: PMC5405729.