Synergistic effect of toosendanin and regorafenib against cell proliferation and migration by regulating WWOX signaling pathway in hepatocellular carcinoma
Abstract
Regorafenib (RGF), a second‐line multi‐kinase inhibitor in the treatment of HCC (hepatocellular carcinoma) after sorafenib failure, exposes to the risk of drug resistance and subsequent progression of HCC patients. Toosendanin (TSN), a triterpenoid has presented excellent inhibition on several tumors. The purpose of this study is to investigate the inhibitory effect of the combination of TSN and RGF on HCC cells. We identified that TSN and RGF combination (TRC) synergistically inhibited the proliferation and migration of MHCC‐97L cells. The upregulation of WWOX (WW‐domain containing oxidoreductase) played a vital role in the HCC cell growth treated with TRC. TRC suppressed the phosphorylation of Stat3 and expression of DVL2, negatively regulated the activity of β‐catenin by promoting the phosphorylation of GSK3β. In addition, the intranuclear proteins, including MMP2, MMP9, and C‐MYC were significantly inhibited by TRC. The in vivo xenograft models confirmed that TRC effectually prevented the tumor growth through upregulating WWOX. Therefore, the treatment of TRC may be a potential solution of RGF resistance and promising therapeutic method in malignant HCC.
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TSN possesses antitumor effects in various cancers by regulating c-Myc, PI3K/AKT/mTOR, and NF-κB, which are strongly correlated with STAT3.
“Recent studies have shown that TSN possesses antitumor effects in various cancers, such as triple-negative breast cancer (TNBC), glioma, ovarian cancer, liver cancer, CRC, by regulating c-Myc, PI3K/AKT/mTOR, and NF-κB, which are strongly correlated with STAT3 (52–55).”
From Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer (2022) · cites this paper as [55]
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Jin, J., Wu, Y., Zhao, Z., Wu, Y., Zhou, Y.-D., Liu, S., Sun, Q., Yang, G., Lin, J., Nagle, D. G., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.160606 · Cited by 57 · see citing works
- Authors
- Yang, T., Huo, J., Xu, R., & Zhang, Y.
- Affiliations
- Xi'an Jiaotong University (CN)
- Corresponding author
- Zhang, Yanmin
- Venue
- Phytotherapy Research
- Publisher
- Wiley
- Published
- 2021-05-31
- Volume
- 35
- Issue
- 8
- Pages
- 4567-4578
- ISSN
- 0951-418X (ISSN-L)
- 1099-1573
- OpenAlex
- W3164687910
- Cited by
- 11
- References
- 0
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 3 · 2023: 1 · 2022: 2
- FWCI
- 0.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Phytotherapy Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fundamental Research Funds for the Central Universities (xtr0118022)
- National Natural Science Foundation of China (81773772)
- Topics
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
- Keywords
- toosendanin, regorafenib, hepatocellular carcinoma, WWOX, synergistic drug combination, STAT3 phosphorylation, GSK3β, β-catenin, DVL2, MMP-2, MMP-9, c-Myc, cell proliferation, cell migration, drug resistance, triterpenoids, multikinase inhibitor
- MeSH terms
- WW Domain-Containing Oxidoreductase, Animals, Drugs, Chinese Herbal, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Phenylurea Compounds, Pyridines, Triterpenes, Signal Transduction, Apoptosis, Xenograft Model Antitumor Assays, Tumor Suppressor Proteins, Glycogen Synthase Kinase 3, Cell Line, Tumor, Cell Proliferation
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