Luteolin Impacts on the DNA Damage Pathway in Oral Squamous Cell Carcinoma

ABSTRACT

Oral squamous cell carcinoma (OSCC) exhibited high chemoresistance to current treatments. Here we aimed at identifying and repositioning approved drugs that could be selectively toxic toward OSCC cells. Through a cell-based drug screening of 1,280 chemical molecules, we selected compounds lethal to oral cancer SCC-25 cells, while sparing normal keratinocyte HaCaT cells. Within the chemical library, the natural flavonoid luteolin was identified as a potent cytotoxic agent against oral cancer cells in vitro, along with metixene hydrochloride and nitazoxanide. Of note, they exhibit low toxicity and high efficiency compared to the standard-of-care, such as cisplatin and the epidermal growth factor receptor inhibitor tyrphostin. From a molecular standpoint, luteolin causes phosphorylation of ataxia telangiectasia mutated (ATM) and H2AX in a DNA repair pathway and can be efficiently combined with a checkpoint kinase (CHK) pharmacological inhibitor. Thus, luteolin emerges as a potent cytotoxic and/or adjuvant therapy in oral cancer, as it is a natural compound presenting better effects in vitro compared to conventional chemotherapeutic agents. Future in vivo exploration is next required to provide the proof-of-concept that luteolin could be an efficient anticancer molecule.

Acknowledgments

We would like to thank the past and present members of SOAP Team laboratory, especially Nicolas Bidère and Eva Galan-Moya.

Funding

This research was funded by Fondation pour la Recherche Medicale, Institut National du Cancer INCA_6508, Ligue nationale contre le cancer comite de Loire-Atlantique and Sarthe, Region Pays-de-la-Loire, Nantes Metropole, and Coordenaçao de Aperfeicoamento de Pessoal de Nivel Superior (#2788-13-6).