Pharmacological Ascorbate Induces Transient Hypoxia Sensitizing Pancreatic Ductal Adenocarcinoma to a Hypoxia Activated Prodrug.

ABSTRACT: Hypoxic tumor microenvironments pose a significant challenge in cancer treatment. Hypoxia-activated prodrugs like evofosfamide aim to specifically target and eliminate these resistant cells. However, their effectiveness is often limited by reoxygenation after cell death. We hypothesized that ascorbate's pro-oxidant properties could be harnessed to induce transient hypoxia, enhancing the efficacy of evofosfamide by overcoming reoxygenation. To test this hypothesis, we investigated the sensitivity of MIA Paca-2 and A549 cancer cells to ascorbate in vitro and in vivo. Ascorbate induced a cytotoxic effect at 5 mM that could be alleviated by endogenous administration of catalase, suggesting a role for hydrogen peroxide in its cytotoxic mechanism. In vitro, Seahorse experiments indicated generat

SUBMITTER: Kishimoto S 

PROVIDER: S-EPMC12478372 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature