Enhancing the Norepinephrine Transporter Expression and [²¹¹At]MABG Uptake with Vorinostat Preloading in the...

Targeted α-radionuclide therapy (TAT) is a promising cancer therapy using α-emitters. However, therapeutic efficacy varies due to differences in the pharmacokinetics of TAT agents among patients. Vorinostat, a histone deacetylase inhibitor, is known to upregulate drug transporter expression, enhance the cellular uptake of β-emitting radiopharmaceuticals, and increase their antitumor efficacy. However, effective strategies or agents to enhance the tumor accumulation of TAT agents remain poorly understood. In this study, we focused on meta-[²¹¹At]At-astatobenzylguanidine ([²¹¹At]MABG) and investigated the potential utility of combining [²¹¹At]MABG with vorinostat. We evaluated protein expression of the norepinephrine transporter (NET), which is critical for the uptake of [²¹¹At]MABG, by immunoblotting in rat pheochromocytoma PC-12 cells and mouse embryonic fibroblast NIH/3T3 cells following vorinostat treatment. The synthesis of [²¹¹At]MABG was performed as previously described, and its cellular uptake was compared between vorinostat-treated and untreated cells. The cytotoxic effect was evaluated using MTT (3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) staining. NET expression in PC-12 cells increased from 24 h after vorinostat treatment, reaching approximately 2.8-fold at 48 h compared to control. No change in NET expression was observed in NIH/3T3 cells after vorinostat treatment. The cellular uptake of [²¹¹At]MABG in PC-12 cells increased by approximately 1.4-fold at 24 h post-vorinostat treatment. Moreover, colony growth of PC-12 cells after 24 h exposure to [²¹¹At]MABG was significantly reduced when combined with vorinostat. In conclusion, vorinostat increased NET expression and enhanced accumulation of [²¹¹At]MABG in pheochromocytoma. In addition, the combination of vorinostat and [²¹¹At]MABG significantly enhanced cytotoxicity. These results suggest that vorinostat is potentially beneficial in optimizing [²¹¹At]MABG therapy.