Institute of Biopharmaceutical and Health Engineering, Shenzhen Key Laboratory of Gene and Antibody Therapy, State Key Laboratory of Chemical Oncogenomics, Tsinghua University Shenzhen International Graduate School, University Town, Nanshan, Shenzhen 518055, China.
Guangdong Clinical Translational Center for Targeted Drug, Department of Pharmacology, School of Medicine, and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, No. 601 Huangpu Avenue West, Tianhe District, Guangzhou 510632, China.
Phytomedicine. 2024 Jul 25;130:155745. doi: 10.1016/j.phymed.2024.155745. Epub 2024 May 18.
Isogarcinol, a natural compound extracted from the fruits of Garcinia oblongifolia, has potential chemopreventive activity. This study aimed to elucidate the anti-tumor effects and mechanism of action of isogarcinol on nasopharyngeal carcinoma (NPC).
Isogarcinol was isolated from Garcinia oblongifolia by using chromatographic separation. The anti-tumor effects of isogarcinol in NPC cells were tested by MTT assay, flow cytometry, wound healing assay, western blotting, transwell assay, colony formation assay, immunofluorescence, and transmission electron microscopy (TEM). The anti-tumor efficacy in vivo was evaluated in NPC cells xenograft models.
Functional studies revealed that isogarcinol inhibited the proliferation, colony formation, migration and invasion abilities of NPC cells in vitro. Isogarcinol caused mitochondrial damage to overproduce reactive oxygen species through reducing the mitochondrial membrane potential and ΔΨm. Isogarcinol also substantially inhibited NPC cells growth in a xenograft tumor model without any obvious toxicity when compared with paclitaxel (PTX). Mechanistic studies have illustrated that isogarcinol increased the Bax/Bcl-2 ratio, cleaved caspase-3, and cytoplasmic cytochrome C levels to induce mitochondrial apoptosis. The ROS overproduction by isogarcinol could suppress EMT pathway via decreasing the levels of p-Akt and Snail. Furthermore, isogarcinol promoted the conversion of LC3-Ⅰ to LC3-Ⅱ, but increased p62 level to block autophagic flux, resulting in the accumulation of damaged mitochondria to promote autophagic cell death in NPC cells.
This study provides a new theoretical foundation for the anti-tumor application of Garcinia oblongifolia and confirms that isogarcinol could be developed as a candidate drug for NPC treatment with low toxicity.
异戈林醇是从藤黄科藤黄属植物椭圆叶省藤的果实中提取的一种天然化合物，具有潜在的化学预防活性。本研究旨在阐明异戈林醇对鼻咽癌（NPC）的抗肿瘤作用及其作用机制。
采用色谱分离法从椭圆叶省藤中分离出异戈林醇。采用 MTT 法、流式细胞术、划痕愈合试验、western blot 法、transwell 试验、集落形成试验、免疫荧光法和透射电镜（TEM）检测异戈林醇对 NPC 细胞的抗肿瘤作用。在 NPC 细胞异种移植模型中评价其体内抗肿瘤疗效。
功能研究表明，异戈林醇抑制 NPC 细胞在体外的增殖、集落形成、迁移和侵袭能力。异戈林醇通过降低线粒体膜电位和ΔΨm 导致线粒体损伤，从而过度产生活性氧。与紫杉醇（PTX）相比，异戈林醇在异种移植肿瘤模型中对 NPC 细胞生长的抑制作用明显，且无明显毒性。机制研究表明，异戈林醇通过增加 Bax/Bcl-2 比值、切割 caspase-3 和细胞质细胞色素 C 水平诱导线粒体凋亡。异戈林醇产生的 ROS 过度表达通过降低 p-Akt 和 Snail 的水平抑制 EMT 途径。此外，异戈林醇促进 LC3-Ⅰ向 LC3-Ⅱ的转化，但增加 p62 水平以阻断自噬流，导致受损线粒体在 NPC 细胞中积累，从而促进自噬性细胞死亡。
本研究为藤黄属植物的抗肿瘤应用提供了新的理论基础，并证实异戈林醇可作为 NPC 治疗的候选药物，具有低毒性。
