Two novel SHP-1 agonists, SC-43 and SC-78, are more potent than regorafenib in suppressing the in vitro stemness of human colorectal cancer cells
| Autor: | Jung Chen Su, Pei Rong Lin, Yeu Su, Ta Chung Chao, Yen Hsi Chen, Chung Wai Shiau, Shin Yi Chung |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Immunology lcsh:RC254-282 Article 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound 0302 clinical medicine Cancer stem cell Regorafenib medicine Viability assay lcsh:QH573-671 STAT3 biology Chemistry lcsh:Cytology CD44 Cancer Cell Biology medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens In vitro 030104 developmental biology Cell culture 030220 oncology & carcinogenesis biology.protein Cancer research |
| Zdroj: | Cell Death Discovery, Vol 4, Iss 1, Pp 1-12 (2018) Cell Death Discovery |
| ISSN: | 2058-7716 |
| DOI: | 10.1038/s41420-018-0084-z |
| Popis: | Signal transducer and activator of transcription 3 (STAT3) has been shown to play a critical role in the maintenance of cancer stem cells (CSCs). Hence, the inhibition of STAT3 signaling has been suggested to be a viable therapeutic approach for cancers. Moreover, the efficacy of combinations of chemotherapeutic drugs and napabucasin, a small-molecule STAT3 inhibitor, have been assessed in various clinical trials, including those involving patients with metastatic colorectal cancer (CRC).Two recently developed small-molecule STAT3 inhibitors, SC-43 and SC-78, which can stimulate SHP-1 to inactivate STAT3, were found to have anti-tumor activity. In this study, the inhibitory effects of SC-43, SC-78, and regorafenib (a reference drug) on cell viability, STAT3 phosphorylation, and various stemness properties [e.g., sphere-forming and soft agar colony-forming abilities, CD133+/CD44+ (stem cell-like) subpopulations, and the expression of several CSC markers] were examined for both HCT-116 and HT-29 human CRC cells. We found that SC-43 and SC-78 but not regorafenib inhibited constitutive and IL-6-induced STAT3 phosphorylation in HCT-116 and HT-29 cells, respectively. Moreover, SC-43 and SC-78 were more potent than regorafenib in suppressing the stemness properties (except stem cell-like subpopulations) of these cells. As expected, SHP-1 knockdown almost completely abolished the suppressive effects of SC-43 and SC-78 on the sphere formation in both cell lines. Furthermore, SC-43 and SC-78 showed synergistic inhibitory effects with oxaliplatin and/or irinotecan on sphere formation. Overall, our results suggest that SC-43 and SC-78 are potent STAT3 inhibitors that may potentially be used in combination therapy for CRC. |
| Databáze: | OpenAIRE |
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