Modulating the Transport of Thiol-Containing Molecules for the Treatment of Lung Diseases and Cancer

NJH ID: 02-16

Summary
National Jewish scientists have identified families of compounds that can increase the transport of thiol-containing molecules, like glutathione, from the cell. Cystic fibrosis and a number of inflammatory lung diseases share a diminished level of glutathione in the epithelial lining fluid and excessive lung inflammatory response. The compounds identified have shown to increase endogenous glutathione in the epithelial lining fluid and therefore could decrease oxidative damage in these diseases. Increasing glutathione efflux is also beneficial in sensitizing cancer cells to anti-cancer agents that cause oxidative damage. These discoveries form the basis of a novel drug discovery platform that modulates oxidative stress in human disease.

Treatment with these compounds in mice increased the levels of glutathione in the extracellular compartment and the lung epithelial lining fluid (ELF). Significant multidrug resistance-associated proteins-specific efflux of glutathione has also been demonstrated in cancer cell lines with a concomitant potentiation of cisplatin cytotoxicity.

 

Potential Applications
Lung diseases, such as cystic fibrosis, chronic beryllium disease, sarcoidosis, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, chronic obstructive lung diseases, idiopathic interstitial pneumonia, and diffuse fibrosing alveolitis.

Adjuvant therapeutic in radiation or chemotherapy treatment for cancer.

 

Advantages of Invention
Many of the compounds are well known and characterized, including one that is currently approved and marketed for unrelated indications.

Compartment and tissue specific secretion of thiol-containing molecules.
An improvement over treatment with exogenous glutathione, which has a short half-life, poor bioavailability, and a lack of stability.

 

State of Development
In mice, treatment with these compounds increased the levels of glutathione in the extracellular compartment and the lung epithelial lining fluid (ELF). Significant MRP-specific efflux of glutathione has also been demonstrated in cancer cell lines with a concomitant potentiation of cisplatin cytotoxicity.

 

Further R&D Required
Additional in vivo studies with other animal models.

 

Publications 

  • Day BJ et al. Infect Immun. 2004 Apr; 72(4):2045-51. PMID: 15039325

  • Day BJ et al. Am J Physiol Lung Cell Mol Physiol. 2001 Jul; 281(1):L31-8. PMID: 11404242

  • Kachadourian et al. Int J Oncol. 2007 Jul; 31(1):161-8. PMID: 17549417

  • Kachadourian et al. Biochem Pharmacol. 2007 Dec 15; 74(12):1677-85. Epub 2007 May 21. PMID: 17585883

  • Kachadourian et al. Free Rad Bio & Med 2006; 41:65-76. PMID: 16781454

 

Patent Status
Issued U.S. Patent #7,498,047
Published U.S. Patent Application #20060135585; International Publication #WO2004/042020; other U.S. and international patents pending. 

 

Inventors
Brian Day, PhD, Leonard Velsor, PhD and Remy Kachadourian, PhD 

 

Licensing Status
This technology is available for licensing.

 

For Further Information, Contact:
Emmanuel Hilaire, PhD
Manager, Technology Transfer Office
National Jewish Health
1400 Jackson Street, Room M206b
Denver, CO 80206
Voice: 303.398.1262
Fax: 303.270.2352
HilaireE@njhealth.org

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