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A Danshensu-Tetramethylpyrazine Conjugate DT-010 Overcomes Multidrug Resistance in Human Breast Cancer
Xinhua Zhou1; Anqi Wang1,2; Liang Wang3; Jianhua Yin4,5; Li Wang6; Lijun Di6; Maggie Pui-Man Hoi1; Luchen Shan7; Xu Wu4,5; Yuqiang Wang7
2019-06-26
Source PublicationFRONTIERS IN PHARMACOLOGY
ISSN1663-9812
Volume10
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-Dimethylthiazol2-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.

KeywordDanshensu Tetramethylpyrazine Breast Cancer Resistance Glycolysis P-glycoprotein
DOI10.3389/fphar.2019.00722
Indexed BySCI
Language英语
WOS Research AreaPharmacology & Pharmacy
WOS SubjectPharmacology & Pharmacy
WOS IDWOS:000473089000001
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Document TypeJournal article
CollectionFaculty of Health Sciences
Corresponding AuthorLuchen Shan; Xu Wu
Affiliation1.State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China
2.PU-UM Innovative Institute of Chinese Medical Sciences, Zhuhai, China
3.Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, China
4.Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
5.South Sichuan Institute of Translational Medicine, Luzhou, China
6.Faculty of Health Sciences, University of Macau, Macao, China
7.Institute of New Drug Research, College of Pharmacy, Jinan University, Guangzhou, China
First Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Xinhua Zhou,Anqi Wang,Liang Wang,et al. A Danshensu-Tetramethylpyrazine Conjugate DT-010 Overcomes Multidrug Resistance in Human Breast Cancer[J]. FRONTIERS IN PHARMACOLOGY,2019,10.
APA Xinhua Zhou.,Anqi Wang.,Liang Wang.,Jianhua Yin.,Li Wang.,...&Yuqiang Wang.(2019).A Danshensu-Tetramethylpyrazine Conjugate DT-010 Overcomes Multidrug Resistance in Human Breast Cancer.FRONTIERS IN PHARMACOLOGY,10.
MLA Xinhua Zhou,et al."A Danshensu-Tetramethylpyrazine Conjugate DT-010 Overcomes Multidrug Resistance in Human Breast Cancer".FRONTIERS IN PHARMACOLOGY 10(2019).
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