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

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 in vitro and in vivo. 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 LKB1fl/flp53fl/fl -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 LKB1fl/flp53fl/fl -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 LKB1fl/flp53fl/fl -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.

Duke Scholars

Author Angeles Alvarez Secord Obstetrics and Gynecology, Gynecologic Oncology