| Status | 已發表Published |
| A Danshensu-Tetramethylpyrazine Conjugate DT-010 Overcomes Multidrug Resistance in Human Breast Cancer. | |
Zhou, X ; Wang, A; WANG, L; YIN, J; Wang, L.; Di, L.; Shan, L ; WU, X
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| 2019-06-26 | |
| Source Publication | Front Pharmacol
 |
| ISSN | 1663-9812 |
| Pages | 1-11 |
| Abstract | Background: We previously demonstrated that a Danshensu-Tetramethylpyrazine conjugate DT-010 enhanced anticancer effect of doxorubicin (Dox) in Dox-sensitive human breast cancer cells, and protected against Dox-induced cardiotoxicity. This work was designed to see whether DT-010 overcomes Dox resistance in resistant human breast cancer cells. Methods: The effects of DT-010, Dox or their combination on cell viability of Dox-resistant human breast cancer MCF-7/ADR cells were conducted using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was examined by flow cytometry after Annexin V-FITC/PI co-staining. Dox accumulation in MCF-7/ADR cells was detected by flow cytometry and fluorescence microscopy. A fluorometric multidrug resistance (MDR) assay kit was used to evaluate the effect of DT-010 on MDR transporter activity. P-glycoprotein (P-gp) expression and activity were analyzed by Western blot and rhodamine 123 (Rh123) efflux assay, respectively. The effects of DT-010 on glycolysis and mitochondrial stress were detected using an Extracellular Flux Analyzer. A Succinate Dehydrogenase Activity Assay kit was used to measure mitochondrial complex II activity. Results: At non-cytotoxic concentrations, DT-010 in combination with Dox led to a significant growth inhibition of MCF-7/ADR cells, suggesting a synergy between DT-010 and Dox to reverse Dox resistance. DT-010 restored Dox-mediated apoptosis and p53 induction in MCF-7/ADR cells. DT-010 increased Dox accumulation in MCF-7/ADR cells via inhibiting P-gp activity, but without changing P-gp expression. Further studies showed that DT-010 significantly inhibited glycolysis and mitochondrial function of MCF-7/ADR cells. Mitochondrial complex II activity was inhibited by DT-010 or DT-010/Dox combination, but not by Dox. The DT-010-mediated suppression of metabolic process may render cells more vulnerable to Dox treatment and thus result in enhanced efficacy. Conclusions: The results indicate that DT-010 overcomes Dox resistance in human breast cancer cells through a dual action via simultaneously inhibiting P-gp-mediated drug efflux and influencing metabolic process. |
| Keyword | P-glycoprotein breast cancer danshensu glycolysis resistance tetramethylpyrazine |
| URL | View the original |
| Language | 英語English |
| The Source to Article | PB_Publication |
| PUB ID | 45219 |
| Document Type | Journal article |
| Collection | DEPARTMENT OF BIOMEDICAL SCIENCES |
| Corresponding Author | Shan, L; WU, X |
| Recommended Citation GB/T 7714 | Zhou, X,Wang, A,WANG, L,et al. A Danshensu-Tetramethylpyrazine Conjugate DT-010 Overcomes Multidrug Resistance in Human Breast Cancer.[J]. Front Pharmacol, 2019, 1-11. |
| APA | Zhou, X., Wang, A., WANG, L., YIN, J., Wang, L.., Di, L.., Shan, L., & WU, X (2019). A Danshensu-Tetramethylpyrazine Conjugate DT-010 Overcomes Multidrug Resistance in Human Breast Cancer.. Front Pharmacol, 1-11. |
| MLA | Zhou, X,et al."A Danshensu-Tetramethylpyrazine Conjugate DT-010 Overcomes Multidrug Resistance in Human Breast Cancer.".Front Pharmacol (2019):1-11. |
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