High-dose Ascorbate Exhibits Anti-proliferative and Anti-invasive Effects Dependent on PTEN/AKT/mTOR Pathway in Endometrial Cancer <i>in vitro</i> and<i> in vivo</i>

Endometrial cancer (EC) is the most common gynecological malignancy, frequently characterized by PTEN deletion, activation of the AKT/mTOR pathway, and limited effective treatment options for recurrent and advanced patients. High-dose ascorbate or combined with other chemotherapeutic agents shows potent antitumor effects <i>in vitro</i> and <i>in vivo</i>. In this study, high-dose ascorbate significantly inhibited cell proliferation and invasion, increased cellular stress and DNA damage, and induced cell cycle arrest and apoptosis in EC cells. Oral or intraperitoneal injections of high-dose ascorbate for 4 weeks effectively inhibited tumor growth in <i>LKB1^fl/flp53^fl/fl</i> -mouse model of EC, with intraperitoneal injections being more effective than oral administration. N-acetylcysteine partially reversed the antitumor effects of ascorbate in EC cells and tumor growth in <i>LKB1^fl/flp53^fl/fl</i> -mice. PTEN knockdown by shRNA reduced the antitumor sensitivity of EC cells to ascorbate, while inhibition of the AKT/mTOR pathway by Ipatasertib significantly enhanced the antitumor activity of ascorbate in EC cells. Ascorbate combined with paclitaxel synergistically inhibited tumor growth compared to either agent alone in <i>LKB1^fl/flp53^fl/fl</i> -mice. Overall, high-dose ascorbate exhibits antitumor activity partially through PTEN/AKT/mTOR and cell stress pathways, and these antitumor effects were heightened when combined with paclitaxel in EC. Clinical trials of ascorbate combined with paclitaxel deserve further investigation in EC patients.