Department of Pharmacy, Anhui Provincial Hospital, Anhui Medical University, Hefei, Anhui, 230001, China.
Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China.
Drug Dev Res. 2022 Feb;83(1):119-130. doi: 10.1002/ddr.21850. Epub 2021 Jun 28.
Tumor cells exhibit higher glycolysis and rely on abnormal energy metabolism to produce ATP, which is essential for cell proliferation and migration. Abnormal energy metabolism inhibition is considered a promising tumor treatment strategy. Xanthatin is an active sesquiterpene lactone isolated from Xanthium strumarium L. This study evaluated the effect of xanthatin on the energy metabolism of human colon cancer cells. The results showed that xanthatin significantly inhibited the migration and invasion of human HT-29 and HCT-116 colon cancer cells. We found that xanthatin effectively reduced the production of ATP and promoted the accumulation of lactate. Xanthatin inhibited glycolysis which may be related to the reduction of glucose transporter 1 (Glut1) and monocarboxylate transporter 4 (MCT4) mRNA and protein levels. Concomitantly, xanthatin promoted complex II activity and oxidative phosphorylation (OXPHOS), resulting in mitochondrial damage and cell death in HT-29 cells. Furthermore, xanthatin inhibited the phosphorylation of mTOR, the phosphorylation of 4E-binding protein 1 (4E-BP1) and c-myc in HT-29 cells. Moreover, rapamycin, a mTOR inhibitor, could enhance the cytotoxicity effect in xanthatin treated HT-29 cells. Additionally, HT-29 cells transfected with si-mTOR aggravated xanthatin induced cell viability inhibition. Based on these results, we observed that the effect of xanthatin on energy metabolism may be related to its inhibition of the mTOR signaling pathway. Collectively, this study provides important insights into xanthatin's anticancer effect, which occurs by regulation of the energy metabolism of human colon cancer cells, and suggest that xanthatin has potential as a botanical drug against abnormal tumor energy metabolism.
肿瘤细胞表现出更高的糖酵解活性，并依赖异常的能量代谢来产生 ATP，这对于细胞增殖和迁移至关重要。抑制异常能量代谢被认为是一种有前途的肿瘤治疗策略。苍术苷是从苍耳属植物中分离得到的一种活性倍半萜内酯。本研究评估了苍术苷对人结肠癌细胞能量代谢的影响。结果表明，苍术苷显著抑制人 HT-29 和 HCT-116 结肠癌细胞的迁移和侵袭。我们发现苍术苷有效地减少了 ATP 的产生并促进了乳酸的积累。苍术苷抑制糖酵解，这可能与葡萄糖转运蛋白 1（Glut1）和单羧酸转运蛋白 4（MCT4）mRNA 和蛋白水平的降低有关。同时，苍术苷促进了复合物 II 的活性和氧化磷酸化（OXPHOS），导致 HT-29 细胞中线粒体损伤和细胞死亡。此外，苍术苷抑制 HT-29 细胞中 mTOR 的磷酸化、4E 结合蛋白 1（4E-BP1）的磷酸化和 c-myc 的磷酸化。此外，mTOR 抑制剂雷帕霉素可增强苍术苷处理的 HT-29 细胞的细胞毒性作用。此外，用 si-mTOR 转染的 HT-29 细胞加重了苍术苷诱导的细胞活力抑制。基于这些结果，我们观察到苍术苷对能量代谢的影响可能与其抑制 mTOR 信号通路有关。总之，本研究为苍术苷对人结肠癌细胞能量代谢的调节作用提供了重要的见解，并表明苍术苷作为一种针对异常肿瘤能量代谢的植物药具有潜力。
