Mitochondria in oral cancer stem cells: Unraveling the potential drug targets for new and old drugs.

Head and neck cancer is a major health problem worldwide, with most cases arising in the oral cavity. Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer, accounting for over 90% of all cases. Compared to other types of cancer, OSCC, has the worse prognosis, with a 5-year survival rate of 50%. Additionally, OSCC is characterized by a high rate of resistance to chemotherapy treatment, which may be partly explained by the presence of cancer stem cells (CSC) subpopulation. CSC can adapt to harmful environmental condition and are highly resistant to both chemotherapy and radiotherapy treatments, thus contributing to tumor relapse. The aim of this review is to highlight the role of mitochondria in oral CSC as a potential target for oral cancer treatment. For this purpose, we reviewed some fundamental aspects of the most validated protein markers of stemness, autophagy, the mitochondrial function and energy metabolism in oral CSC. Moreover, a discussion will be made on why energy metabolism, especially oxidative phosphorylation in CSC, may offer such a diverse source of original pharmacological target for new drugs. Finally, we will describe some drugs able to disturb mitochondrial function, with emphasis on those aimed to interrupt the electron transport chain function, as novel therapeutic strategies in multidrug-resistant oral CSC. The reutilization of old drugs approved for clinical use as new antineoplastics, in cancer treatment, is also matter of revision.