Shen Fei, Zheng Yun-Sheng, Dong Lan, Cao Ziyang, Cao Jie
Department of General Surgery, The First Affiliated Hospital, Jinan University, Guangzhou, China.
Department of General Surgery, Guangzhou Digestive Disease Center, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China.
Front Pharmacol. 2024 Nov 1;15:1500731. doi: 10.3389/fphar.2024.1500731. eCollection 2024.
Colorectal cancer (CRC) stands as the third most widespread cancer globally with poor prognosis. Berberine (Ber), as one herbal phytochemical, showed promise in CRC therapy, but its exact mechanism is unclear. Small molecule traditional drugs face challenges in quick metabolism and low bio-availability after systemic administration. Nanodrug deliver system, with their unique properties, has the advantages of protecting drugs, improving drug bio-availability, and reducing toxic and side effects, which exhibited huge drug delivery potential. Herein, the PEG-PLGA nanocarrier was used for encapsulated Ber according to nanoprecipitation and obtained nanomedicine, denoted as NPBer. , the flow cytometry test and CCK8 assays indicated that NPBer was more easily taken up by HCT116 CRC cells, and had stronger inhibition on cell proliferation with the increase of drug concentration. In addition, RNA-Seq was employed to explore the alterations in the transcriptomes of cancer cells subsequent to treatment with Free Ber or NPBer.The sequencing results indicate that Free Ber could activate cellular aging mechanisms, intensified the iron death pathway, optimized oxidative phosphorylation efficiency, exacerbated apoptosis, accelerated programmed cell death, and negatively modulated key signaling pathways in CRC cells including Wnt, TGF-beta, Hippo, and mTOR signaling pathways. Based on PEG-PLGA nanocarriers, NPBer can improve the delivery efficiency of Ber, thereby enhancing its antitumor efficacy , enhancing apoptosis by enhancing the mitochondrial autophagy and autophagy activities of CRC cells, negatively regulating the inflammatory mediator to regulate TRP channels, and inhibiting the activation of Notch signaling pathway. , NPBer can significantly improve its accumulation and durable drug targeting in tumor site, resulting in induce maximum cell apoptosis and effectively inhibit the proliferation of HCT116 tumor. This strategy provided a promising antitumor therapeutic strategy using Ber-based drugs.
结直肠癌（CRC）是全球第三大常见癌症，预后较差。小檗碱（Ber）作为一种植物化学物质，在CRC治疗中显示出前景，但其确切机制尚不清楚。小分子传统药物在全身给药后面临代谢快和生物利用度低的挑战。纳米药物递送系统具有独特的性质，具有保护药物、提高药物生物利用度和减少毒副作用的优点，展现出巨大的药物递送潜力。在此，采用纳米沉淀法将PEG-PLGA纳米载体用于包裹Ber，得到纳米药物，记为NPBer。流式细胞术检测和CCK8分析表明，NPBer更容易被HCT116 CRC细胞摄取，并且随着药物浓度的增加对细胞增殖的抑制作用更强。此外，采用RNA-Seq来探索游离Ber或NPBer处理后癌细胞转录组的变化。测序结果表明，游离Ber可激活细胞衰老机制，强化铁死亡途径，优化氧化磷酸化效率，加剧细胞凋亡，加速程序性细胞死亡，并对CRC细胞中的关键信号通路包括Wnt、TGF-β、Hippo和mTOR信号通路产生负调控。基于PEG-PLGA纳米载体，NPBer可提高Ber的递送效率，从而增强其抗肿瘤疗效，通过增强CRC细胞的线粒体自噬和自噬活性来增强细胞凋亡，负向调节炎症介质以调节TRP通道，并抑制Notch信号通路的激活。此外，NPBer可显著提高其在肿瘤部位的蓄积和持久的药物靶向性，从而诱导最大程度的细胞凋亡并有效抑制HCT116肿瘤的增殖。该策略为使用基于Ber的药物提供了一种有前景的抗肿瘤治疗策略。
