Scoulerine: A natural isoquinoline alkaloid targeting SLC6A3 to treat RCC

• Published in: Biomedicine & pharmacotherapy 2024-11, Vol.180, p.117524, Article 117524
• Main Authors: Qu, Tianrui, Sun, Yu, Zhao, Jingying, Liu, Nanqi, Yang, Jianli, Lyu, Dantong, Huang, Wenjie, Zhan, Weizhen, Li, Tao, Yao, Zichuan, Yan, Rongbo, Zhang, Haiyan, Hong, Hong, Shi, Liye, Meng, Xin, Yin, Bo
• Format: Article
• Language: English
• Subjects: Alkaloids - pharmacology; Animals; Apoptosis; Apoptosis - drug effects; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; Cell Line, Tumor; Cell Survival - drug effects; Humans; Isoquinolines - pharmacology; Isoquinolines - therapeutic use; Kidney Neoplasms - drug therapy; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; MAP Kinase Signaling System - drug effects; Mice; Mice, Nude; Mitogen activated protein kinase signaling pathway; Renal cell carcinoma; Scoulerine; Solute Carrier Family 6 Member 3; Xenograft Model Antitumor Assays
• ISSN: 0753-3322; 1950-6007; 1950-6007
• DOI: 10.1016/j.biopha.2024.117524

Scoulerine, an isoquinoline alkaloid derived from the corydalis plant, exhibits diverse therapeutic properties against tumors, Alzheimer's disease, and inflammation. This research delves into the pharmacological impact and underlying mechanism of scoulerine on renal cell carcinoma (RCC). Our findings suggest that Scoulerine displays promise as a potential therapeutic agent for RCC, demonstrating notable inhibitory effects in both in vivo and in vitro models. In addition, scoulerine inhibited the viability of 769-P and 786-O cell lines in a time-dependent and dose-dependent manner, and promoted the level of apoptosis associated with B-cell lymphoma-2 associated X protein (Bax). Moreover, the administration of scoulerine resulted in a significant suppression of the mitogen activated protein kinase (MAPK) signaling pathway. Subsequently, utilizing bioinformatics and spatial transcriptomic databases, we identified solute carrier family 6 Member 3 (SLC6A3) as the most promising target of scoulerine. Through experimental validation, we confirmed the functional and therapeutic relevance of SLC6A3 in scoulerine-mediated treatment of RCC. The results of our study indicate a significant affinity between scoulerine and SLC6A3, with competitive inhibition of this interaction leading to a reduction in the inhibitory impact of scoulerine on RCC cell viability. In conclusion, our findings suggest that scoulerine may induce apoptosis in RCC by targeting SLC6A3 and inhibiting the activation of the MAPK signaling pathway, thereby positioning it as a promising natural compound for potential future RCC treatment. [Display omitted] •Scoulerine effectively treats renal cell carcinoma by promoting apoptosis.•Scoulerine's therapeutic effect on RCC is due to its reduction of key protein phosphorylation in the MAPK signaling pathway.•Binding to SLC6A3 is a key mechanism through which scoulerine provides therapeutic effects for RCC.