Byun Woong Sub, Bae Eun Seo, Kim Won Kyung, Lee Sang Kook
Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
J Nat Prod. 2022 May 27;85(5):1407-1418. doi: 10.1021/acs.jnatprod.2c00224. Epub 2022 May 11.
Alkaloids derived from natural products have been traditionally used to treat various diseases, including cancers. Rutaecarpine (), a β-carboline-type alkaloid obtained from , has been previously reported as an anti-inflammatory agent. Nonetheless, its anticancer activity and the underlying molecular mechanisms remain to be explored. In the procurement of Wnt/β-catenin inhibitors from natural alkaloids, was found to exhibit activity against the Wnt/β-catenin-response reporter gene. Since the abnormal activation of Wnt/β-catenin signaling is highly involved in colon carcinogenesis, the antitumor activity and molecular mechanisms of were investigated in colorectal cancer (CRC) cells. The antiproliferative activity of was associated with the suppression of the Wnt/β-catenin-mediated signaling pathway and its target gene expression in human CRC cells. also induced G/G cell cycle arrest and apoptotic cell death, and the antimigration and anti-invasion potential of was confirmed through epithelial-mesenchymal transition biomarker inhibition by the regulation of Wnt signaling. The antitumor activity of was supported in an Ls174T-implanted xenograft mouse model via Wnt target gene regulation. Overall, these findings suggest that targeting the Wnt/β-catenin signaling pathway by is a promising therapeutic option for the treatment of human CRC harboring β-catenin mutation.
天然产物衍生的生物碱传统上用于治疗包括癌症在内的各种疾病。吴茱萸次碱（），一种从 中获得的β-咔啉类生物碱，先前已被报道为一种抗炎剂。然而，其抗癌活性及潜在的分子机制仍有待探索。在从天然生物碱中筛选Wnt/β-连环蛋白抑制剂的过程中，发现 对Wnt/β-连环蛋白反应报告基因具有活性。由于Wnt/β-连环蛋白信号通路的异常激活与结肠癌发生高度相关，因此在结直肠癌（CRC）细胞中研究了 的抗肿瘤活性及分子机制。 在人CRC细胞中的抗增殖活性与Wnt/β-连环蛋白介导的信号通路及其靶基因表达的抑制有关。 还诱导G/G细胞周期阻滞和凋亡性细胞死亡，并且通过Wnt信号调节对上皮-间质转化生物标志物的抑制作用证实了 的抗迁移和抗侵袭潜能。 在Ls174T植入的异种移植小鼠模型中通过Wnt靶基因调节支持了 的抗肿瘤活性。总体而言，这些发现表明， 通过靶向Wnt/β-连环蛋白信号通路是治疗携带β-连环蛋白突变的人CRC的一种有前景的治疗选择。
