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Reversal effect of quercetin on multidrug resistance via FZD7/β-catenin pathway in hepatocellular carcinoma cells.
Phytomedicine. 2018 Apr 01; 43:37-45.P

Abstract

BACKGROUND

Chemotherapy has been widely used to treat cancer, but the appearance of multidrug resistance (MDR) is the biggest obstacle to successful chemotherapy. One of the conventional mechanisms of MDR is overexpression of ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp/ABCB1) and multidrug resistance-associated proteins (MRPs/ABCCs) that limits the prolonged and efficient use of chemotherapeutic drugs. To enhance the chemosensitivity of tumor cells, attentions have been focused on effective MDR modulators.

PURPOSE

This study aimed to investigate the reversal effect of quercetin on MDR, and explored its mechanism of action in vitro.

STUDY DESIGN/METHODS

The effect and mechanism of quercetin on MDR was examined by using MTT assay, flow cytometry, real-time PCR and western blot analysis in human hepatocellular carcinoma cells.

RESULTS

Our data found that the intracellular accumulation of rhodamine-123 (Rh123) and doxorubicin (ADR) were increased, the sensitivity of BEL/5-FU cells to chemotherapeutic drugs were increased, and the expressions of ABCB1, ABCC1 and ABCC2 were all down-regulated, which indicated that the functions and expressions of ABCB1, ABCC1 and ABCC2 efflux pump were inhibited by quercetin treatment. Moreover, the suppression of ABCB1, ABCC1 and ABCC2 by quercetin was dependent on the FZD7 through the Wnt/β-catenin pathway. Further research revealed that reduction of FZD7 by RNA interference (siFZD7) enhanced the sensitivity to chemotherapeutic drugs, increased the cellular accumulation of Rh123 and ADR, and induced inhibitory effects on the expression of FZD7, ABCB1, ABCC1, ABCC2 and β-catenin, similar to quercetin. In the meanwhile, overexpression of FZD7 showed the inversely effect on the expressions. Interesting, it was confirmed that quercetin could inhibit the expression levels of FZD7, ABCB1, ABCC1, ABCC2 and β-catenin in BEL-7402 cells; furthermore, treatment by quercetin combined with siFZD7 in BEL/5-FU cells, the expressions of these genes were effectively decreased in comparison to quercetin combined with siRNA negative control (sncRNA).

CONCLUSION

Overall, these data suggested the effectiveness of using quercetin, at least in part, via inhibiting FZD7 to combat chemoresistance and showed that quercetin could be developed into an efficient natural sensitizer for resistant human hepatocellular carcinoma.

Authors+Show Affiliations

Institute for Liver Diseases of Anhui Medical University (AMU), Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, China; Department of Pharmacy, Anhui Provincial Hospital, Anhui Medical University, Hefei, Anhui 230001, China.Institute for Liver Diseases of Anhui Medical University (AMU), Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, China.Institute for Liver Diseases of Anhui Medical University (AMU), Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, China.Department of Pharmacy, Anhui Provincial Hospital, Anhui Medical University, Hefei, Anhui 230001, China.Department of Pharmacy, Anhui Provincial Hospital, Anhui Medical University, Hefei, Anhui 230001, China.Department of Pharmacy, Anhui Provincial Hospital, Anhui Medical University, Hefei, Anhui 230001, China.Department of Pharmacy, Anhui Provincial Hospital, Anhui Medical University, Hefei, Anhui 230001, China.Department of Pharmacy, Anhui Provincial Hospital, Anhui Medical University, Hefei, Anhui 230001, China.Department of Pharmacy, Anhui Provincial Hospital, Anhui Medical University, Hefei, Anhui 230001, China.Institute for Liver Diseases of Anhui Medical University (AMU), Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, China. Electronic address: lj@ahmu.edu.cn.Department of Pharmacy, Anhui Provincial Hospital, Anhui Medical University, Hefei, Anhui 230001, China. Electronic address: anhuiaizongs@163.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29747752

Citation

Chen, Zhaolin, et al. "Reversal Effect of Quercetin On Multidrug Resistance Via FZD7/β-catenin Pathway in Hepatocellular Carcinoma Cells." Phytomedicine : International Journal of Phytotherapy and Phytopharmacology, vol. 43, 2018, pp. 37-45.
Chen Z, Huang C, Ma T, et al. Reversal effect of quercetin on multidrug resistance via FZD7/β-catenin pathway in hepatocellular carcinoma cells. Phytomedicine. 2018;43:37-45.
Chen, Z., Huang, C., Ma, T., Jiang, L., Tang, L., Shi, T., Zhang, S., Zhang, L., Zhu, P., Li, J., & Shen, A. (2018). Reversal effect of quercetin on multidrug resistance via FZD7/β-catenin pathway in hepatocellular carcinoma cells. Phytomedicine : International Journal of Phytotherapy and Phytopharmacology, 43, 37-45. https://doi.org/10.1016/j.phymed.2018.03.040
Chen Z, et al. Reversal Effect of Quercetin On Multidrug Resistance Via FZD7/β-catenin Pathway in Hepatocellular Carcinoma Cells. Phytomedicine. 2018 Apr 1;43:37-45. PubMed PMID: 29747752.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Reversal effect of quercetin on multidrug resistance via FZD7/β-catenin pathway in hepatocellular carcinoma cells. AU - Chen,Zhaolin, AU - Huang,Cheng, AU - Ma,Taotao, AU - Jiang,Ling, AU - Tang,Liqin, AU - Shi,Tianlu, AU - Zhang,Shantang, AU - Zhang,Lei, AU - Zhu,Pengli, AU - Li,Jun, AU - Shen,Aizong, Y1 - 2018/03/19/ PY - 2017/09/22/received PY - 2018/01/26/revised PY - 2018/03/18/accepted PY - 2018/5/12/entrez PY - 2018/5/12/pubmed PY - 2018/8/31/medline KW - ATP-binding cassette transporters, FZD7/β-catenin pathway KW - Hepatocellular carcinoma KW - Multiple drug resistance KW - Quercetin SP - 37 EP - 45 JF - Phytomedicine : international journal of phytotherapy and phytopharmacology JO - Phytomedicine VL - 43 N2 - BACKGROUND: Chemotherapy has been widely used to treat cancer, but the appearance of multidrug resistance (MDR) is the biggest obstacle to successful chemotherapy. One of the conventional mechanisms of MDR is overexpression of ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp/ABCB1) and multidrug resistance-associated proteins (MRPs/ABCCs) that limits the prolonged and efficient use of chemotherapeutic drugs. To enhance the chemosensitivity of tumor cells, attentions have been focused on effective MDR modulators. PURPOSE: This study aimed to investigate the reversal effect of quercetin on MDR, and explored its mechanism of action in vitro. STUDY DESIGN/METHODS: The effect and mechanism of quercetin on MDR was examined by using MTT assay, flow cytometry, real-time PCR and western blot analysis in human hepatocellular carcinoma cells. RESULTS: Our data found that the intracellular accumulation of rhodamine-123 (Rh123) and doxorubicin (ADR) were increased, the sensitivity of BEL/5-FU cells to chemotherapeutic drugs were increased, and the expressions of ABCB1, ABCC1 and ABCC2 were all down-regulated, which indicated that the functions and expressions of ABCB1, ABCC1 and ABCC2 efflux pump were inhibited by quercetin treatment. Moreover, the suppression of ABCB1, ABCC1 and ABCC2 by quercetin was dependent on the FZD7 through the Wnt/β-catenin pathway. Further research revealed that reduction of FZD7 by RNA interference (siFZD7) enhanced the sensitivity to chemotherapeutic drugs, increased the cellular accumulation of Rh123 and ADR, and induced inhibitory effects on the expression of FZD7, ABCB1, ABCC1, ABCC2 and β-catenin, similar to quercetin. In the meanwhile, overexpression of FZD7 showed the inversely effect on the expressions. Interesting, it was confirmed that quercetin could inhibit the expression levels of FZD7, ABCB1, ABCC1, ABCC2 and β-catenin in BEL-7402 cells; furthermore, treatment by quercetin combined with siFZD7 in BEL/5-FU cells, the expressions of these genes were effectively decreased in comparison to quercetin combined with siRNA negative control (sncRNA). CONCLUSION: Overall, these data suggested the effectiveness of using quercetin, at least in part, via inhibiting FZD7 to combat chemoresistance and showed that quercetin could be developed into an efficient natural sensitizer for resistant human hepatocellular carcinoma. SN - 1618-095X UR - https://www.unboundmedicine.com/medline/citation/29747752/Reversal_effect_of_quercetin_on_multidrug_resistance_via_FZD7/β_catenin_pathway_in_hepatocellular_carcinoma_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0944-7113(18)30075-8 DB - PRIME DP - Unbound Medicine ER -