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.

Doxycycline hyclate是四环素的衍生物，具有抗炎和抗菌活性。 Doxycycline hyclate 是一种具有口服活性的广谱金属蛋白酶 (MMP) 抑制剂^[5]。Doxycycline hyclate 治疗可降低 MMP-8 和 -9 水平并抑制组织 MMP-2 和 MMP-9 的表达。此外，用盐酸多西环素治疗可显着降低颅内动脉瘤的发生率。据报道，多西环素海克酸盐是一种基于其对基质金属蛋白酶的抑制作用的抗炎剂。此外，多西环素具有有效的抗疟活性，体外96h的IC₅₀值为320nM^{[2 3]}。

Doxycycline hyclate 在体外以温度依赖性方式抑制登革热病毒复制。 IC₅₀ 值在 37°C 时为 52.3μM，在 40°C 时为 26.7μM。它通过抑制病毒的NS2B-NS3丝氨酸蛋白酶来抑制登革热病毒^[5]

盐酸多西环素在胶质瘤和星形胶质细胞中引起严重线粒体核蛋白失衡的能力，尤其是在高浓度时。在常规用于诱导基因表达的浓度下，强力霉素海克酸盐对细胞生长没有影响。只有最高测试浓度的盐酸多西环素 (10 ug/mL) 会损害细胞生长^[4]。在人类细胞系中，常用浓度的盐酸多西环素会改变基因表达模式，并伴随着将新陈代谢向更快速的方向转变糖酵解表型，表现为乳酸分泌增加和耗氧量减少[7]。多西环素可抑制乳腺癌细胞和 BCSCs 的活力和增殖，降低乳腺球形成效率、迁移和侵袭以及乳腺癌细胞的 EMT。多西环素hyclate处理后干细胞因子的表达也显着下调^[8]

在 P. berghei 疟疾小鼠模型中，盐酸多西环素在 50 mg/kg 时表现出有效的抗疟活性，而在 10 mg/kg 时活性次优 ^[1]。盐酸多西环素处理抑制组织 MMP 并减弱胶原蛋白 III 单倍体不足的小鼠主动脉中胶原蛋白含量的减少，并防止应激诱导的血管病理学的发展。结果表明，盐酸多西环素作为治疗 vEDS（埃勒斯-当洛斯综合征的血管形式）值得进行临床试验^[6]