Abstract P2-05-07: Combination treatment to prevent and treat oxidative damage to neuronal cells

Abstract Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting side-effect of taxanes, platinum agents, vinca alkaloids, bortezomib and thalidomide. These regimens are first-line treatment for common cancers such as breast, colorectal, lung and lymphoma and used in both early-stage and metastatic cancer therapy. Therefore, numerous patients, both young and old, are at risk for developing CIPN. The symptoms have a negative impact on routine activities, functions, and behaviors in the domestic, work, and social lives of cancer patients, adversely affecting the quality of their survivorship. A meta-analysis of 31 CIPN studies revealed an aggregated prevalence of 48%. In contrast to other adverse effects, such as hematological side effects, the symptoms of CIPN can be irreversible and there are currently no effective managements to prevent, alleviate or reverse these symptoms. As the number of cancer survivors increases, new research needs to focus on prevention and treatment of this long-term adverse effect to improve patients’ function and quality-of-life. We have previously shown that personal biochemical responses to oxidative stress, induced by chemotherapeutic agents, during the early cycles of treatment are associated with development of CIPN. Therefore, we have tested a series of antioxidants and components of neuronal signaling transduction for their ability to prevent and/or reverse damage induced by oxidative stress in neuronal cell cultures. Methods: All experiments were performed using the well-defined mouse neuronal model cell-line Neuro2A and the human peripheral nerve sheath cell-line S462. Cells were treated with retinoic acid in low serum conditions to induce differentiation prior to experiments. Oxidative stress was induced by adding hydrogen peroxide to cultures pre- or post-addition of antioxidant agents at various concentrations. Differentiation was followed by microscopy to determine neurite outgrowth and cell counts to demonstrate cell cycle exit. Cell viability and membrane damage was tested using the MTT and LDH assays, respectively. PCR and Western blotting was performed to examine changes in KEAP-NRF2 pathway, Caspase-3, SOD, and NLRP3 using commercially available antibodies and reagents. Results: To date, we have test the monosialoglycospingolipid, GM1, and two antioxidants, not listed by ASCO as unsuitable for prevention/treatment of CIPN, for their effect on hydrogen peroxide triggered neuronal cell damage. Damage to mouse Neuro2A cells could not be prevented or rescued by single agent treatment at doses ranging from 10μM to 50μM. However, when combining GM1 with one of the antioxidants, all doses were able to prevent damage while high dose could treat existing cell damage. Cell damage to the human S462 could be prevented and treated if using high dose GM1 as single agent. In contrast to the Neuro2A experiments, when combining with GM1 with an antioxidant all doses ranging from 10μM to 50μM had a therapeutic effect. The strongest response was observed using the combination treatment in both cell lines. Discussion and Conclusions: We have been using GM1, a well-tolerated agent, but with reported mixed responses in clinical trials when used to prevent or treat CIPN. Based on our previous data and reports in the literature demonstrating the possible initiation of cell damage resulting in CIPN by oxidative stress, we have performed as series of test using GM1 as single agent and in combination with known antioxidants in cell culture experiment to select optimal treatment options prior to testing in animal models. Using existing therapeutic agents with low toxicity profiles could result in a rapid transition into clinical use for prevention and/or treatment of CIPN for cancer patients. Citation Format: Matthew Koury, Kathryn J. Fleck, Alisha P. Maity, Zonera A. Ali, Erik L. Zeger, Aarti L. Shevade, Arezoo Ghaneie, Deric C. Savior, U. Margaretha Wallon. Combination treatment to prevent and treat oxidative damage to neuronal cells [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-05-07.