2846 - Old Wine in a New Bottle: The Antimycotic Agent Oxiconazole and PRDX2-Mediated Ferroptosis in NSCLC

X. Liu¹, J. Yuan², Q. Li², J. Yu³, and D. Chen⁴; ¹Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China, ²Shandong cancer hospital, Jinan, China, ³Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China, ⁴Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China

Purpose/Objective(s): Drug repurposing, which refers to identifying new indications of approved or investigational drugs, is an effective strategy for drug discovery. Oxiconazole (OXI), a broad-spectrum antifungal compound, is currently extensively utilized for the treatment of fungal infections. Recent work from our lab has shown that OXI can improve radiosensitivity and anti-tumor effect by enhancing ferroptosis in vivo and in vitro assays. Thus, we aim to explore the mechanisms involved, which may provide the molecular basis for applying OXI as a potential radiosensitizer to combine with radiotherapy. Materials/

Methods: The A549 and H1299 cells were exposed to equal doses of X-rays in order to establish cell lines with increased resistance to radiation. The expression and function of PRDX2 was assessed via immunostaining, real-time PCR, western blot, a 5-ethynyl-2-deoxyuridine assay and a radiation clonogenic assay. Ferroptosis was determined by detecting glutathione, lipid peroxidation, malondialdehyde and ferrous ion levels. The in vivo effects of PRDX2 were examined with OXI treatment or lentivirus modification of PRDX2 expression in radiated mouse models.
Results: We identified a novel role of PRDX2 in promoting the radioresistance of cancer cells. PRDX2 were highly expressed in radioresistant cancer cells. PRDX2 knockdown increased cell survival (P < 0.05), and elevated ferroptosis and oxidative stress (P < 0.05) after X-ray radiation. Ferroptosis inhibitor attenuated radioresistance (P < 0.05) caused by PRDX2 overexpression. Molecular docking assays suggested OXI towards PRDX2. The OXI treatment of tumor cell lines overexpressing PRDX2 effectively suppressed radioresistance and enhanced ferroptosis after irradiation. The mouse models with PRDX2 overexpression subcutaneous tumors showed that OXI combined with irradiation enhanced control of solid tumor growth, accompanied by increased the expression of ferroptosis-promoting proteins by immunohistochemistry.
Conclusion: Our study demonstrates that ferroptosis induced by PRDX2 inhibition may be the primary contributing factor for growth suppression in response to OXI combine with radiotherapy. These findings provide novel evidence into the mechanism of action of OXI, implying OXI as a potential radiosensitizer for cancer radiotherapy and highlighting the concept that ferroptosis may hold promise as a therapeutic target in cancer.