Identification of ferroptosis as a novel mechanism for antitumor activity of natural product derivative a2 in gastric cancer
| Autor: | Zan Song, De-Quan Yu, Hong-Min Liu, Wang Wang, Yu Ke, Xu-Bin Ma, Ying Liu, Yajie Liu, Yi-Chao Xu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Programmed cell death
DCFH-DA dichlorodihydro-fluorescein diacetate qRT-PCR quantitative real time PCR NAC N-acetylcysteine RM1-950 GPX4 KEGG Kyoto Encyclopedia of Genes and Genomes PK pharmacokinetic Lipid peroxidation Papp apparent permeability coefficient 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine ROS reactive oxygen species Downregulation and upregulation medicine Autophagy Ferroptosis PDX patient-derived tumor xenograft RTV relative tumor volume General Pharmacology Toxicology and Pharmaceutics JDA Jiyuan oridonin A PARP poly ADP-ribose polymerase 030304 developmental biology 0303 health sciences Cell growth Jiyuan Rabdosia rubescens Cancer ROS medicine.disease Verp verapamil DCM dichloromethane chemistry IKE imidazole ketone erastin JDA derivative 030220 oncology & carcinogenesis Cancer cell CDX cell line-derived xenograft Cancer research Ferrous iron Original Article 5-FU 5-fluorouracil Therapeutics. Pharmacology Gastric cancer |
| Zdroj: | Acta Pharmaceutica Sinica B, Vol 11, Iss 6, Pp 1513-1525 (2021) Acta Pharmaceutica Sinica. B |
| ISSN: | 2211-3835 |
| Popis: | Ferroptosis is a type of cell death accompanied by iron-dependent lipid peroxidation, thus stimulating ferroptosis may be a potential strategy for treating gastric cancer, therapeutic agents against which are urgently required. Jiyuan oridonin A (JDA) is a natural compound isolated from Jiyuan Rabdosia rubescens with anti-tumor activity, unclear anti-tumor mechanisms and limited water solubility hamper its clinical application. Here, we showed a2, a new JDA derivative, inhibited the growth of gastric cancer cells. Subsequently, we discovered for the first time that a2 induced ferroptosis. Importantly, compound a2 decreased GPX4 expression and overexpressing GPX4 antagonized the anti-proliferative activity of a2. Furthermore, we demonstrated that a2 caused ferrous iron accumulation through the autophagy pathway, prevention of which rescued a2 induced ferrous iron elevation and cell growth inhibition. Moreover, a2 exhibited more potent anti-cancer activity than 5-fluorouracil in gastric cancer cell line-derived xenograft mice models. Patient-derived tumor xenograft models from different patients displayed varied sensitivity to a2, and GPX4 downregulation indicated the sensitivity of tumors to a2. Finally, a2 exhibited well pharmacokinetic characteristics. Overall, our data suggest that inducing ferroptosis is the major mechanism mediating anti-tumor activity of a2, and a2 will hopefully serve as a promising compound for gastric cancer treatment. Graphical abstract Natural product derivative, a2, exhibited anti-tumor activity by inducing ferroptosis through decreasing GPX4 and causing ferrous iron accumulation in gastric cancer cells.Image 1 |
| Databáze: | OpenAIRE |
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