Artesunate targets oral tongue squamous cell carcinoma via mitochondrial dysfunction-dependent oxidative damage and Akt/AMPK/mTOR inhibition.

Although mitochondrial metabolism has recently gained attention as a promising therapeutic strategy in cancer, little is known on the impact of mitochondrial respiration inhibition on oral tongue squamous cell carcinoma (OTSCC). Using in vitro and in vivo OTSCC models, our work demonstrates that inducing mitochondrial dysfunction by anti-malarial drug artesunate is effective in targeting OTSCC stem-cell like and bulk cells. Artesunate inhibits anchorage-independent colony formation, proliferation and survival in all tested OTSCC cell lines although with varying efficacy. Artesunate displays preferential anti-OTSCC activity by sparing normal cells. Mechanism analysis indicates that artesunate inhibits mitochondrial respiration via suppressing mitochondrial complex I and II but not IV or V, resulting in oxidative stress and damage. Interestingly, OTSCC cells that are more sensitive to artesunate have higher level of basal mitochondrial respiration and reversed respiratory capacity compared to those with less sensitivity to artesunate, suggesting the varying dependence on mitochondrial respiration among OTSCC cell lines. In addition, artesunate induces oxidative stress and damage in cells with low sensitivity to a less extent than in those with high sensitivity. We confirm that mitochondrial respiration inhibition is required for the action of artesunate in OTSCC. Mitochondrial dysfunction by artesunate further activates AMPK and suppresses Akt/mTOR. Importantly, the in vitro observations are reproducible in vivo OTSCC xenograft mouse model. Our findings provide pre-clinical evidence on the efficacy of artesunate and emphasize the therapeutic value of targeting mitochondrial respiration in OTSCC.