Experimental Study on the Treatment of Norepinephrine Transporter-Overexpressing Pheochromocytomas and paragangliomas: A Synthetic Lethality Strategy Combining 131I-MIBG with PARP Inhibitors

JiePing Song^1,2Lulu zhang^1,2Fan Qiu^1,2Xiumin Shi^1,2Rui Tian^1,2Chuan Zhang^1,2Xiaoyuan Li^1,2Feng Wang^1,2*

• ¹Nanjing First Hospital, Nanjing, China
• ²Nanjing Medical University, Nanjing, China

Introduction: Pheochromocytomas and paragangliomas (PPGLs) are associated with poor prognosis especially in patients with metastatic spread. This study aims to investigate the therapeutic potential of 131I-MIBG and the PARP inhibitor fluzoparib monotherapies and their combination on two distinct PC12-derived stable cell lines: PC12-NET cells and PC12-NET-SDHB cells. Methods: Lentiviral transduction was used to generate PC12-NET cells overexpressing the norepinephrine transporter (NET) and PC12-NET-SDHB cells with suppressed succinate dehydrogenase subunit B (SDHB) expression. The specificity of PC12-NET cells to the 131I-MIBG was confirmed through desipramine inhibition assays. Subsequently, the synergistic effects of 131I-MIBG and fluzoparib monotherapies and their combination were assessed in vitro through proliferation assays, cell cycle analysis and apoptosis analysis in both cell lines. Results: NET overexpression significantly enhanced 131I-MIBG uptake in PC12-NET cells, confirming NET expression as a critical determining of 131I-MIBG therapeutic efficacy. The combination of 131I-MIBG with fluzoparib exhibited substantial synergistic effects in PC12-NET cells, leading to a significant G2/M phase arrest and a marked increase in apoptosis compared to monotherapy, particularly where monotherapy alone was ineffective. Notably, although low expression of the SDHB did not alter cell proliferation in response to 131I-MIBG treatment, PC12-NET-SDHB cells exhibited a greater sensitivity to fluzoparib-induced G2/M phase arrest than PC12-NET cells. Discussion: The combined of 131I-MIBG with PARP inhibitor demonstrated a synergistic antitumor effect in PC12-NET cells. While PC12-NET-SDHB cells display comparable sensitivity to 131I-MIBG as PC12-NET cells, they exhibited heightened responsiveness to PARP inhibitor treatment.