- The FDA-approved diabetes drug acetohexamide significantly improves the response of cells that predisposes can increase the risk of skin cancer.
- Patients with the rare genetic disease Xeroderma pigmentosum increase their chances of skin cancer when exposed tot he sun.
- Xeroderma pigmentosum to date lacks any curative treatment though it was identified in 1874.
The rare genetic disease Xeroderma pigmentosum - also known as "Moonchildren' have an increased risk of skin cancer and develop inflammation when exposed to only small amounts of sunlight.
The severe condition is caused by mutations in the genes for the nucleotide excision repair (NER) pathway - the only known mechanism that deals with UV-induced DNA damage in human cells. Although first described in 1874, Xeroderma pigmentosum to date lacks any curative treatment.
‘Anti-diabetic drug acetohexamide can alleviate the sensitivity of NER-deficient cells and enhance the repair of UV lesions in those with Xeroderma pigmentosum.’
Screening For Drugs That Fight Xeroderma pigmentosum
The scientists at CeMM found in their most recent publication that the FDA-approved diabetes drug acetohexamide significantly improves the resilience of NER-deficient cells against UV radiation in vitro
The study identified the responsible molecular mode of action - a hitherto unknown, NER-independent repair mechanism for UV-induced DNA damage. The study has not tested the use of acetohexamide in Xeroderma pigmentosum patients.
In their study, the scientists of Loizou's team developed a special chemical screening approach for compounds that would allow Xeroderma pigmentosum-disease cells to survival UV treatment better.
Using the CLOUD (Cemm Library of Unique Drugs), this approach led to the identification of acetohexamide: By treating Xeroderma pigmentosum-disease cells with the diabetes drug, these cells could now repair UV-induced DNA damage more efficiently.
Acetohexamide Degrades UV-induced DNA damage
A multitude of subsequent experiments eventually led to the elucidation of the underlying molecular mechanism: acetohexamide leads to the degradation of the DNA repair enzyme MUTYH, triggering a hitherto unknown NER-independent mechanism for removing UV-induced DNA damage.
"MUTYH has not been previously implicated in the removal of UV-induced lesions," emphasizes Abdelghani Mazouzi, first author of the study. "However, our data collectively show that the anti-diabetic drug acetohexamide can alleviate the sensitivity of NER-deficient cells and enhance the repair of UV lesions through the degradation of MUTYH."
"Loss of MUTYH allows Xeroderma pigmentosum-disease cells to deal with UV-induced DNA damage more proficiently" Joanna Loizou summarizes.
"Those findings are not only a valuable contribution to the fundamental, molecular understanding of DNA repair but could also pave the way for a novel therapeutic approach for this severe and debilitating disease, for which there is no curative treatment".
- Abdelghani Mazouzi, Federica Battistini, Sarah C. Moser, Joana Ferreira da Silva, Marc Wiedner, Michel Owusu, Charles-Hugues Lardeau, Anna Ringler, Beatrix Weil, Jürgen Neesen, Modesto Orozco, Stefan Kubicek, Joanna I. Loizou7. 'Repair of UV-Induced DNA Damage Independent of Nucleotide Excision Repair Is Masked by MUTYH.' Molecular Cell (2017). http://dx.doi.org/10.1016/j.molcel.2017.10.021.