2,3,5,4′-Tetrahydroxystilbene (TG1), a Novel Compound Derived from 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside (THSG), Inhibits Colorectal Cancer Progression by Inducing Ferroptosis, Apoptosis, and Autophagy

Author:

Tsai Kuei-Yen123ORCID,Wei Po-Li2456ORCID,Lee Cheng-Chin7,Makondi Precious Takondwa8,Chen Hsin-An23,Chang Yao-Yuan9,Liu Der-Zen910,Huang Chien-Yu1112,Chang Yu-Jia161314ORCID

Affiliation:

1. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan

2. Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan

3. Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235041, Taiwan

4. Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan

5. Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei 11031, Taiwan

6. Cancer Research Center and Translational Laboratory, Department of Medical Research, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan

7. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan

8. Kamuzu Central Hospital—National Cancer Center, Lilongwe P.O. Box 149, Malawi

9. Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan

10. Medical and Pharmaceutical Industry Technology and Development Center, New Taipei 24888, Taiwan

11. School of Medicine, National Tsing Hua University, Hsinchu 300044, Taiwan

12. Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 300044, Taiwan

13. Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan

14. Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan

Abstract

Background: Colorectal cancer (CRC) is one of the deadliest cancers worldwide and long-term survival is not guaranteed in metastatic disease despite current multidisciplinary therapies. A new compound 2,3,5,4′-Tetrahydroxystilbene (TG1), derived from THSG (2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-Glucoside), has been developed, and its anticancer ability against CRC is verified in this study. Methods: HCT116, HT-29, and DLD-1 were treated with TG1 and the IC50 was measured using a sulforhodamine B assay. A Xenograft mouse model was used to monitor tumor growth. Apoptosis and autophagy, induced by TG1 in CRC cells, were examined. RNA-sequencing analysis of CRC cells treated with TG1 was performed to discover underlying pathways and mechanisms. Results: The results demonstrated that treatment with TG1 inhibited CRC proliferation in vitro and in vivo and induced apoptotic cell death, which was confirmed by Annexin V-FITC/PI staining and Western blotting. Additionally, TG1 treatment increased the level of autophagy in cells. RNA-sequencing and GSEA analyses revealed that TG1 was associated with MYC and the induction of ferroptosis. Furthermore, the ferroptosis inhibitor Bardoxolone abrogated the cytotoxic effect of TG1 in CRC cells, indicating that ferroptosis played a crucial role in TG1-induced cytotoxicity. Conclusions: These findings suggest that TG1 might be a potential and potent compound for clinical use in the treatment of CRC by inhibiting proliferation and inducing ferroptosis through the MYC pathway.

Funder

Taipei Medical University

Publisher

MDPI AG

Subject

General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)

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