Melatonin mitigates UV-induced tumorigenesis and suppresses hearing function deterioration in Xpa-deficient mice

Abstract

Background: Xeroderma pigmentosum (XP) is caused by impaired DNA repair of UV-induced dipyrimidine-photoproducts. XP cells also show impaired repair/removal of ROS or oxidative DNA lesions caused by UV or 4-nitroquinolline 1-oxide (4NQO). Gene profiling indicated that inflammatory response-related genes are significantly upregulated after UV exposure in XP-A model mice.

Objective: Since XP cells are in the state of oxidative stress and inflammation, we aimed to search for therapeutic agents from anti-oxidants/anti-inflammatory drugs, that potentially improve XP symptoms.

Methods: Several antioxidants were examined for reducing 4NQO-induced oxidative cytotoxicity or UV-induced oxidative DNA damage in XP-A cells. Among them, we focused on melatonin and evaluated its improving effect for Xpa-deficient MEF on UV-induced cytotoxicity and ROS production, and for Xpa-deficient mice on UV-induced skin tumorigenesis and auditory brainstem responses as one of the neurological symptoms.

Results: Melatonin and nicotinamide attenuated 4NQO-induced oxidative cytotoxicity. UV-induced intracellular ROS production and cytotoxicity were improved by melatonin for Xpa-deficient MEF. Finally, the administration of melatonin mitigated UV-induced skin inflammation and tumorigenesis and suppressed hearing deterioration in Xpa-deficient mice.

Conclusion: Our results show that melatonin could alleviate XP symptoms through its anti-inflammatory and antioxidant properties.

Keywords: Auditory brainstem responses; Melatonin; Nucleotide excision repair; Ultraviolet radiation; Xeroderma pigmentosum.