Increasing The Efficacy Of Antitumor Therapy: A Lysine Specific Demethylase 1 Inhibitor In Combination With 5-Deoxyazacytidine

Elizabeth Grant

School Name

South Carolina Governor's School for Science and Mathematics

Grade Level

12th Grade

Presentation Topic

Biochemistry

Presentation Type

Mentored

Mentor

Mentor: Patrick Woster, Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina

Abstract

Lysine-specific demethylase 1 (LSD1) is a chromatin remodeling oxidase enzyme that is over expressed in a number of human cancers. It has been targeted for the development of specific inhibitors with therapeutic potential. LSD1 has been shown that the interactions between histones and chromatin remodeling are very important for selective control of gene expression. Because of this, chromatin remodeling enzymes are very quickly becoming attractive therapeutic targets for multiple diseases with an epigenetic basis. Through histone and DNA marker changes such as: acetylation, methylation, and sumoylation, certain genes can be turned “on” or “off.” LSD1 acts as a dethmethylase enzyme and removes methyl groups from the mono- and dimethylated forms of histone 3 lysine 4 (H3K4). Demethylation of mono- and dimethylated H3K4 results in gene silencing. Because H3K4 is over expressed in cancer, important tumor suppressor proteins are not formed. The drug 5-deoxyazacytidine is a standard therapy for lung cancer, but has serious side effects that limit its use. We hypothesized that combining a specific LSD1 inhibitor with 5-deoxyazacytidine would allow the use of a lower dose, reducing side effects. To test this hypothesis, we treated CALU-6 human lung adenocarcinoma cells with novel LSD1 inhibitors combined with various concentrations of 5-deoxyazacytidine. It was discovered that these LSD1 inhibitors had minimal effect on the IC50 of 5-deoxyazacytidine. We concluded that there was no significant difference between the CALU 6 cells that were only dosed with 5-deoxyazacytidine and the ones that were dosed with both a novel LSD1 inhibitor and 5-deoxyazacytidine.

Start Date

4-11-2015 9:30 AM

End Date

4-11-2015 9:45 AM

COinS
 
Apr 11th, 9:30 AM Apr 11th, 9:45 AM

Increasing The Efficacy Of Antitumor Therapy: A Lysine Specific Demethylase 1 Inhibitor In Combination With 5-Deoxyazacytidine

Lysine-specific demethylase 1 (LSD1) is a chromatin remodeling oxidase enzyme that is over expressed in a number of human cancers. It has been targeted for the development of specific inhibitors with therapeutic potential. LSD1 has been shown that the interactions between histones and chromatin remodeling are very important for selective control of gene expression. Because of this, chromatin remodeling enzymes are very quickly becoming attractive therapeutic targets for multiple diseases with an epigenetic basis. Through histone and DNA marker changes such as: acetylation, methylation, and sumoylation, certain genes can be turned “on” or “off.” LSD1 acts as a dethmethylase enzyme and removes methyl groups from the mono- and dimethylated forms of histone 3 lysine 4 (H3K4). Demethylation of mono- and dimethylated H3K4 results in gene silencing. Because H3K4 is over expressed in cancer, important tumor suppressor proteins are not formed. The drug 5-deoxyazacytidine is a standard therapy for lung cancer, but has serious side effects that limit its use. We hypothesized that combining a specific LSD1 inhibitor with 5-deoxyazacytidine would allow the use of a lower dose, reducing side effects. To test this hypothesis, we treated CALU-6 human lung adenocarcinoma cells with novel LSD1 inhibitors combined with various concentrations of 5-deoxyazacytidine. It was discovered that these LSD1 inhibitors had minimal effect on the IC50 of 5-deoxyazacytidine. We concluded that there was no significant difference between the CALU 6 cells that were only dosed with 5-deoxyazacytidine and the ones that were dosed with both a novel LSD1 inhibitor and 5-deoxyazacytidine.