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Schisandrin A reverses doxorubicin-resistant human breast cancer cell line by the inhibition of P65 and Stat3 phosphorylation.
Breast Cancer. 2018 Mar; 25(2):233-242.BC

Abstract

BACKGROUND

Multidrug resistance (MDR) in breast cancer therapy occurs frequently. Thus, anti-MDR agents from natural products or synthetic compounds were tested extensively. We have also explored the reverse effect and mechanism of Schisandrin A (Sch A), a natural product, on MCF-7 breast cancer doxorubicin (DOX)-resistant subline MCF-7/DOX.

METHODS

MTT assay was performed to measure the viability of MCF-7 cells to assess the reverse effect of Sch A. Western blot analysis was used to study the protein levels. Laser scanning confocal microscopy was performed to detect the intercellular DOX and Rhodamine 123 accumulation. The qRT-PCR was used to analysis the target gene expression. Dual-luciferase reporter assay was performed to test the transcriptional activity of P-glycoprotein (P-gp).

RESULTS

Sch A, at the concentration of 20 µM, showed selective reverse effect (better than the positive control, verapamil at 5 µM) on MCF-7/DOX cell line but not on BEL-7402/DOX, Hep G2/DOX, and K-562/DOX cells. In addition, Sch A enhanced DOX-induced cleavage of Caspase-9 and PARP levels by increasing intracellular DOX accumulation and inhibiting P-gp function. Furthermore, Sch A selectively suppressed P-gp at gene and protein levels in MCF-7/DOX cells which express high level of MDR1 but not MRP1, MRP3, or BCRP. Besides, Sch A showed inhibitory effect on P-gp transcriptional activity. Sch A significantly reduced p-IκB-α (Ser32) and p-Stat3 (Tyr705) levels which mediate P-gp expression. In addition, Stat3 knockdown enhanced the reverse effect of siP65. The combined effect of siStat3 and siP65 was better than Sch A single treatment in MCF-7/DOX cells.

CONCLUSION

Sch A specifically reverses P-gp-mediated DOX resistance in MCF-7/DOX cells by blocking P-gp, NF-κB, and Stat3 signaling. Inhibition of P65 and Stat3 shows potent anti-MDR effect on MCF-7/DOX cells.

Authors+Show Affiliations

Department of Pharmacy, Linyi People's Hospital, Linyi, Shandong, China.Department of Pharmacy, First People's Hospital of Tancheng County, Tancheng, Shandong, China.Department of Gynecology and Obstetrics, Linyi People's Hospital, 27# Jie fang lu dong duan, Linyi, Shandong, China. wangsrpaper@sina.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29181822

Citation

Zhang, Zong-Lin, et al. "Schisandrin a Reverses Doxorubicin-resistant Human Breast Cancer Cell Line By the Inhibition of P65 and Stat3 Phosphorylation." Breast Cancer (Tokyo, Japan), vol. 25, no. 2, 2018, pp. 233-242.
Zhang ZL, Jiang QC, Wang SR. Schisandrin A reverses doxorubicin-resistant human breast cancer cell line by the inhibition of P65 and Stat3 phosphorylation. Breast Cancer. 2018;25(2):233-242.
Zhang, Z. L., Jiang, Q. C., & Wang, S. R. (2018). Schisandrin A reverses doxorubicin-resistant human breast cancer cell line by the inhibition of P65 and Stat3 phosphorylation. Breast Cancer (Tokyo, Japan), 25(2), 233-242. https://doi.org/10.1007/s12282-017-0821-9
Zhang ZL, Jiang QC, Wang SR. Schisandrin a Reverses Doxorubicin-resistant Human Breast Cancer Cell Line By the Inhibition of P65 and Stat3 Phosphorylation. Breast Cancer. 2018;25(2):233-242. PubMed PMID: 29181822.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Schisandrin A reverses doxorubicin-resistant human breast cancer cell line by the inhibition of P65 and Stat3 phosphorylation. AU - Zhang,Zong-Lin, AU - Jiang,Qing-Cheng, AU - Wang,Su-Rong, Y1 - 2017/11/27/ PY - 2017/07/03/received PY - 2017/11/15/accepted PY - 2017/11/29/pubmed PY - 2018/8/31/medline PY - 2017/11/29/entrez KW - Doxorubicin KW - Multidrug resistance KW - NF-κB KW - Schisandrin A KW - Stat3 SP - 233 EP - 242 JF - Breast cancer (Tokyo, Japan) JO - Breast Cancer VL - 25 IS - 2 N2 - BACKGROUND: Multidrug resistance (MDR) in breast cancer therapy occurs frequently. Thus, anti-MDR agents from natural products or synthetic compounds were tested extensively. We have also explored the reverse effect and mechanism of Schisandrin A (Sch A), a natural product, on MCF-7 breast cancer doxorubicin (DOX)-resistant subline MCF-7/DOX. METHODS: MTT assay was performed to measure the viability of MCF-7 cells to assess the reverse effect of Sch A. Western blot analysis was used to study the protein levels. Laser scanning confocal microscopy was performed to detect the intercellular DOX and Rhodamine 123 accumulation. The qRT-PCR was used to analysis the target gene expression. Dual-luciferase reporter assay was performed to test the transcriptional activity of P-glycoprotein (P-gp). RESULTS: Sch A, at the concentration of 20 µM, showed selective reverse effect (better than the positive control, verapamil at 5 µM) on MCF-7/DOX cell line but not on BEL-7402/DOX, Hep G2/DOX, and K-562/DOX cells. In addition, Sch A enhanced DOX-induced cleavage of Caspase-9 and PARP levels by increasing intracellular DOX accumulation and inhibiting P-gp function. Furthermore, Sch A selectively suppressed P-gp at gene and protein levels in MCF-7/DOX cells which express high level of MDR1 but not MRP1, MRP3, or BCRP. Besides, Sch A showed inhibitory effect on P-gp transcriptional activity. Sch A significantly reduced p-IκB-α (Ser32) and p-Stat3 (Tyr705) levels which mediate P-gp expression. In addition, Stat3 knockdown enhanced the reverse effect of siP65. The combined effect of siStat3 and siP65 was better than Sch A single treatment in MCF-7/DOX cells. CONCLUSION: Sch A specifically reverses P-gp-mediated DOX resistance in MCF-7/DOX cells by blocking P-gp, NF-κB, and Stat3 signaling. Inhibition of P65 and Stat3 shows potent anti-MDR effect on MCF-7/DOX cells. SN - 1880-4233 UR - https://www.unboundmedicine.com/medline/citation/29181822/Schisandrin_A_reverses_doxorubicin_resistant_human_breast_cancer_cell_line_by_the_inhibition_of_P65_and_Stat3_phosphorylation_ L2 - https://dx.doi.org/10.1007/s12282-017-0821-9 DB - PRIME DP - Unbound Medicine ER -