Nonsteroidal Anti-inflammatory Drugs Modulate Cellular Glycosaminoglycan Synthesis by Affecting EGFR and PI3K Signaling Pathways

Overview

Journal Sci Rep

Specialty Science

Date 2017 Feb 28

PMID 28240227

Citations 8

Authors

Pawel Mozolewski

Marta Moskot

Joanna Jakobkiewicz-Banecka

Grzegorz Wegrzyn

Katarzyna Bochenska

Bogdan Banecki

Magdalena Gabig-Ciminska

Affiliations

Soon will be listed here.

Abstract

In this report, selected non-steroidal anti-inflammatory drugs (NSAIDs), indomethacin and nimesulide, and analgesics acetaminophen, alone, as well as in combination with isoflavone genistein as potential glycosaminoglycan (GAG) metabolism modulators were considered for the treatment of mucopolysaccharidoses (MPSs) with neurological symptoms due to the effective blood-brain barrier (BBB) penetration properties of these compounds. We found that indomethacin and nimesulide, but not acetaminophen, inhibited GAG synthesis in fibroblasts significantly, while the most pronounced impairment of glycosaminoglycan production was observed after exposure to the mixture of nimesulide and genistein. Phosphorylation of the EGF receptor (EGFR) was inhibited even more effective in the presence of indomethacin and nimesulide than in the presence of genistein. When examined the activity of phosphatidylinositol-3-kinase (PI3K) production, we observed its most significant decrease in the case of fibroblast exposition to nimesulide, and afterwards to indomethacin and genistein mix, rather than indomethacin used alone. Some effects on expression of individual GAG metabolism-related and lysosomal function genes, and significant activity modulation of a number of genes involved in intracellular signal transduction pathways and metabolism of DNA and proteins were detected. This study documents that NSAIDs, and their mixtures with genistein modulate cellular glycosaminoglycan synthesis by affecting EGFR and PI3K signaling pathways.

Citing Articles

Potential drugs for the treatment of Alzheimer's disease.

Montero-Cosme T, Pascual-Mathey L, Hernandez-Aguilar M, Herrera-Covarrubias D, Rojas-Duran F, Aranda-Abreu G Pharmacol Rep. 2023; 75(3):544-559.

PMID: 37005970 DOI: 10.1007/s43440-023-00481-5.

Network Pharmacology Integrated with Transcriptomics Analysis Reveals Ermiao Wan Alleviates Atopic Dermatitis via Suppressing MAPK and Activating the EGFR/AKT Signaling.

Xia T, Liang X, Liu C, Hu Y, Luo Z, Tan X Drug Des Devel Ther. 2022; 16:4325-4341.

PMID: 36578822 PMC: 9790806. DOI: 10.2147/DDDT.S384927.

Assessment, pharmacological therapy and rehabilitation management of musculoskeletal pain in children with mucopolysaccharidoses: a scoping review.

Gnasso R, Corrado B, Iommazzo I, Migliore F, Magliulo G, Giardulli B Orphanet J Rare Dis. 2022; 17(1):255.

PMID: 35804400 PMC: 9264657. DOI: 10.1186/s13023-022-02402-w.

Melatonin abolished proinflammatory factor expression and antagonized osteoarthritis progression in vivo.

Liu S, Tsai C, Wang Y, Su C, Wu H, Fong Y Cell Death Dis. 2022; 13(3):215.

PMID: 35256585 PMC: 8901806. DOI: 10.1038/s41419-022-04656-5.

Genistein Prevents Hypoxia-Induced Cognitive Dysfunctions by Ameliorating Oxidative Stress and Inflammation in the Hippocampus.

Rumman M, Pandey S, Singh B, Gupta M, Ubaid S, Mahdi A Neurotox Res. 2021; 39(4):1123-1133.

PMID: 33740236 DOI: 10.1007/s12640-021-00353-x.

References

Moskot M, Jakobkiewicz-Banecka J, Smolinska E, Banecki B, Wegrzyn G, Gabig-Ciminska M . Activities of genes controlling sphingolipid metabolism in human fibroblasts treated with flavonoids. Metab Brain Dis. 2015; 30(5):1257-67. PMC: 4560762. DOI: 10.1007/s11011-015-9705-x. View

Rizzo R, Grandolfo M, Godeas C, Jones K, Vittur F . Calcium, sulfur, and zinc distribution in normal and arthritic articular equine cartilage: a synchrotron radiation-induced X-ray emission (SRIXE) study. J Exp Zool. 1995; 273(1):82-6. DOI: 10.1002/jez.1402730111. View

Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43):15545-50. PMC: 1239896. DOI: 10.1073/pnas.0506580102. View

Riley G, Cox M, Harrall R, Clements S, Hazleman B . Inhibition of tendon cell proliferation and matrix glycosaminoglycan synthesis by non-steroidal anti-inflammatory drugs in vitro. J Hand Surg Br. 2001; 26(3):224-8. DOI: 10.1054/jhsb.2001.0560. View

Brady R . Emerging strategies for the treatment of hereditary metabolic storage disorders. Rejuvenation Res. 2006; 9(2):237-44. DOI: 10.1089/rej.2006.9.237. View

Piotrowska E, Jakobkiewicz-Banecka J, Tylki-Szymanska A, Liberek A, Maryniak A, Malinowska M . Genistin-rich soy isoflavone extract in substrate reduction therapy for Sanfilippo syndrome: An open-label, pilot study in 10 pediatric patients. Curr Ther Res Clin Exp. 2014; 69(2):166-79. PMC: 3969963. DOI: 10.1016/j.curtheres.2008.04.002. View

Narajczyk M, Moskot M, Konieczna A . Quantitative estimation of lysosomal storage in mucopolysaccharidoses by electron microscopy analysis. Acta Biochim Pol. 2012; 59(4):693-6. View

Eden E, Navon R, Steinfeld I, Lipson D, Yakhini Z . GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinformatics. 2009; 10:48. PMC: 2644678. DOI: 10.1186/1471-2105-10-48. View

Hoffer L, Kaplan L, Hamadeh M, Grigoriu A, Baron M . Sulfate could mediate the therapeutic effect of glucosamine sulfate. Metabolism. 2001; 50(7):767-70. DOI: 10.1053/meta.2001.24201. View

10.

Liu J, Wu W, Liu S, Zuo L, Wang Y, Yang J . Nimesulide inhibits the growth of human esophageal carcinoma cells by inactivating the JAK2/STAT3 pathway. Pathol Res Pract. 2015; 211(6):426-34. DOI: 10.1016/j.prp.2015.01.007. View

11.

Moskot M, Montefusco S, Jakobkiewicz-Banecka J, Mozolewski P, Wegrzyn A, di Bernardo D . The phytoestrogen genistein modulates lysosomal metabolism and transcription factor EB (TFEB) activation. J Biol Chem. 2014; 289(24):17054-69. PMC: 4059147. DOI: 10.1074/jbc.M114.555300. View

12.

DINGLE J . The effects of NSAID on the matrix of human articular cartilages. Z Rheumatol. 1999; 58(3):125-9. DOI: 10.1007/s003930050161. View

13.

Jakobkiewicz-Banecka J, Piotrowska E, Gabig-Ciminska M, Borysiewicz E, Slominska-Wojewodzka M, Narajczyk M . Substrate reduction therapies for mucopolysaccharidoses. Curr Pharm Biotechnol. 2011; 12(11):1860-5. DOI: 10.2174/138920111798376932. View

14.

van der Kraan P, Vitters E, De Vries B, van den Berg W . High susceptibility of human articular cartilage glycosaminoglycan synthesis to changes in inorganic sulfate availability. J Orthop Res. 1990; 8(4):565-71. DOI: 10.1002/jor.1100080413. View

15.

Wraith J . The first 5 years of clinical experience with laronidase enzyme replacement therapy for mucopolysaccharidosis I. Expert Opin Pharmacother. 2005; 6(3):489-506. DOI: 10.1517/14656566.6.3.489. View

16.

Miura S, Tatsuguchi A, Wada K, Takeyama H, Shinji Y, Hiratsuka T . Cyclooxygenase-2-regulated vascular endothelial growth factor release in gastric fibroblasts. Am J Physiol Gastrointest Liver Physiol. 2004; 287(2):G444-51. DOI: 10.1152/ajpgi.00537.2003. View

17.

Gabig-Ciminska M, Jakobkiewicz-Banecka J, Malinowska M, Kloska A, Piotrowska E, Chmielarz I . Combined Therapies for Lysosomal Storage Diseases. Curr Mol Med. 2015; 15(8):746-71. DOI: 10.2174/1566524015666150921105658. View

18.

Kloska A, Jakobkiewicz-Banecka J, Narajczyk M, Banecka-Majkutewicz Z, Wegrzyn G . Effects of flavonoids on glycosaminoglycan synthesis: implications for substrate reduction therapy in Sanfilippo disease and other mucopolysaccharidoses. Metab Brain Dis. 2011; 26(1):1-8. PMC: 3070076. DOI: 10.1007/s11011-011-9233-2. View

19.

Foucquier J, Guedj M . Analysis of drug combinations: current methodological landscape. Pharmacol Res Perspect. 2015; 3(3):e00149. PMC: 4492765. DOI: 10.1002/prp2.149. View

20.

Beck M . New therapeutic options for lysosomal storage disorders: enzyme replacement, small molecules and gene therapy. Hum Genet. 2006; 121(1):1-22. DOI: 10.1007/s00439-006-0280-4. View