By Riya Gandhi ‘22
In an age in which cancer is the second leading cause of death worldwide, scientists are seeking to discover and develop novel treatments for the disease. Sometimes, although rarely, the answer is just at their fingertips. In a recent study, a team of researchers from the University of Edinburgh sought to understand the mechanism by which 5-nitrofuran antibiotics, also known as pro-drugs, aid in anti-cancer activity.
Under the direction of Dr. Sana Sarvi, researchers sought to further their work on compounds containing 5-nitrofuran target ALDH2. Many cancer cells that have high ADLH (aldehyde dehydrogenase) enzymatic activity are marked as cancer stem cell subpopulations because they have increased potential for tumorigenesis or the formation of a tumor. First, the researchers tested the range of concentrations of drug activity in cancer cells and thereby decided to use antibiotic nifuroxazide as the 5-nitrofuran in the study. After that, the researchers tested the nifuroxazide as a substrate for ALDH1 and ALDH2 in vitro and determined that it was an effective substrate for ALDH1A3, which is an isoform of ALDH1 that is especially expressed in melanoma-initiating cells. Through comparative analysis, the researchers subsequently found that nifuroxazide was a selective substrate for ALDH1. They then determined that out of all other forms of 5-nitrofuran, nifuroxazide is the best substrate for targeting ALDH1. Using molecular modeling and mass spectrometry, the researchers discovered that the bio-activation of nifuroxazide oxidizes and hinders ALDH1 enzymes, which suggests that nifuroxazide not only inhibits these enzymes in cancer cells but also allows for the selective eradication of tumor subpopulations of melanoma cells that express this enzyme.
By targeting cancer cell populations instead of molecular activity in cancer mutations, the researchers in this study broke away from traditional therapy methods. The work of Dr. Sarvi and her fellow researchers has opened the door to even more opportunity and potential in drug-repurposing. In the future, 5-nitrofurans could very well pave the way to improved immunotherapies for not just melanoma but other cancer types as well.
- S. Sarvi, et. al., ALDH1 bio-activates nifuroxazide to eradicate ALDH high melanoma-initiating cells. Cell Chemical Biology (2018). doi: https://doi.org/10.1016/j.chembiol.2018.09.005
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