Berbamine Enhances the Efficacy of Gefitinib by Suppressing STAT3 Signaling in Pancreatic Cancer Cells
| Autor: | Shouzhang Yang, Jinfu Tu, Xiaming Huang, Bingren Hu, Huajie Cai, Gang Chen |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cell cycle checkpoint Cell growth Berbamine Cell cycle 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine Gefitinib Oncology chemistry Apoptosis 030220 oncology & carcinogenesis Cancer research medicine Pharmacology (medical) Clonogenic assay Receptor medicine.drug |
| Zdroj: | OncoTargets and Therapy. 12:11437-11451 |
| ISSN: | 1178-6930 |
| DOI: | 10.2147/ott.s223242 |
| Popis: | Background Small molecular inhibitors such as gefitinib (Gefi), which target EGF receptor (EGFR), are considered to be a viable pathway for the selective inhibition of pancreatic cancer (PC) development. However, the large difference in Gefi response between PC patient individuals and PC cell lines severely limits the clinical efficacy of Gefi. Berbamine (BBM) is a well-known natural-derived antitumor agent. However, no study yet exists on whether BBM can enhance the sensitivity of PC cells to Gefi or its underlying mechanisms. Methods MTS assay and clonogenic assay were used to determine whether BBM could enhance the anti-PC activity of Gefi by. Flow cytometric analysis was performed to study the cell cycle progression and rate of apoptosis after combined treatment with BBM and Gefi. Surface plasmon resonance (SPR) and Western blot experiments were carried out to detect the STAT3 binding affinity and the STAT3 inhibitory effect of BBM. Molecular docking and Molecular dynamic simulation were used to predicting the dominant interaction between BBM and STAT3. Results This study found that BBM synergizes with Gefi to inhibit cell growth and induce cell cycle arrest and PC cell apoptosis. Mechanistically, our results showed that BBM and Gefi have synergistic inhibitory effects on STAT3 phosphorylation, but have little effect on other EGFR downstream pathways, suggesting that BBM may exert sensitization through the inhibition of STAT3. Besides, BBM has a high affinity for STAT3 and a good inhibitory effect on STAT3 activation, further indicating that BBM was a potent direct STAT3 inhibitor. Molecular modeling between STAT3 and BBM suggested that BBM formed several key hydrophilic interactions with STAT3. Conclusion Our findings suggest that the combination of BBM and Gefi could be further developed as a potential PC therapy. |
| Databáze: | OpenAIRE |
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