Abstract 484: Enhancing therapeutic responses in NSCLC using iron-oxide nanoparticles combined with pharmacological ascorbate

Abstract

Abstract High dose Vitamin C (pharmacological ascorbate; P-AscH‒ > 20 mM plasma levels) given intravenously (I.V.), has made a remarkable re-emergence as an adjuvant to combined modality approaches in cancer therapy. P-AscH‒ can be readily oxidized in the presence of redox active metals (i.e., P-AscH‒ serves as an iron reducing agent), which can result in increased fluxes of H2O2. This chemical phenomenon allows for the tumor-selective enhancement of chemo-radiation in NSCLC. We hypothesized that enhancing labile Fe2+ in cancer cells using iron-oxide nanoparticles (ferumoxytol, FMX) can increase the effectiveness of P-AscH‒ in enhancing cancer cell sensitivity to chemo-radiation in NSCLC by increasing H2O2 production. To test this hypothesis, we performed clonogenic cell survival assays in-vitro. To test the role of H2O2 in the combined effect of P-AscH‒ and FMX, we developed lentiviral-based doxycycline-inducible overexpression models for catalase, and to determine the changes in Fe, we used fluorescent probes that specifically detect changes in labile Fe2+. Results from these experiments showed FMX enhanced clonogenic cell killing in NSCLC. Furthermore, catalase overexpression inhibited this effect, suggesting that enhanced H2O2 production plays a central role in the additive effect of P-AscH- and FMX. Finally, staining the cells with the fluorescent iron probes showed that FMX enhanced labile Fe2+ in cells treated with P-AscH‒. These studies continue to support the hypothesis that H2O2 plays a significant role in P-AscH‒ toxicity in cancer cells that can be exacerbated using iron oxide nanoparticles. Future studies will test these findings in-vivo using preclinical xenograft models. (supported by P01 CA217797, P30 CA086862, T32 CA078586, and P01 CA244091). Citation Format: Mekhla Singhania, Miachael S. Petronek, Casey F. Pulliam, Kranti A. Mapuskar, Amira Zaher, Douglas R. Spitz. Enhancing therapeutic responses in NSCLC using iron-oxide nanoparticles combined with pharmacological ascorbate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 484.