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Tetrandrine Interaction with ABCB1 Reverses Multidrug Resistance in Cancer Cells Through Competition with Anti-Cancer Drugs Followed by Downregulation of ABCB1 Expression

1
Key Laboratory for Complementary and Alternative Medicine Experimental Animal Models of Guangxi, Guangxi University of Chinese Medicine, Nanning 530200, China
2
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA
3
Institute of Plastic Surgery, Weifang Medical University, Weifang 261041, China
4
State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, China
*
Authors to whom correspondence should be addressed.
Molecules 2019, 24(23), 4383; https://doi.org/10.3390/molecules24234383
Received: 13 October 2019 / Revised: 25 November 2019 / Accepted: 27 November 2019 / Published: 30 November 2019
(This article belongs to the Section Natural Products Chemistry)
The overexpression of ABC transporters induced by anticancer drugs has been found to be the main cause of multidrug resistance. It is actually also a strategy by which cancer cells escape being killed. Tetrandrine is a natural product extracted from the stem of Tinospora crispa. In this study, tetrandrine showed synergistic cytotoxic activity in combinational use with chemotherapeutic drugs, such as Doxorubicin, Vincristine, and Paclitaxel, in both drug-induced and MDR1 gene-transfected cancer cells that over-expressed ABCB1/P-glycoprotein. Tetrandrine stimulated P-glycoprotein ATPase activity, decreased the efflux of [3H]-Paclitaxel and increased the intracellular accumulation of [3H]-Paclitaxel in KB-C2 cells. Furthermore, SW620/Ad300 and KB-C2 cells pretreated with 1 μM tetrandrine for 72 h decreased P-glycoprotein expression without changing its cellular localization. This was demonstrated through Western blotting and immunofluorescence analysis. Interestingly, down-regulation of P-glycoprotein expression was not correlated with gene transcription, as the MDR1 mRNA level exhibited a slight fluctuation in SW620/Ad300 and KB-C2 cells at 0, 24, 48, and 72 h treatment time points. In addition, molecular docking analysis predicted that tetrandrine had inhibitory potential with the ABCB1 transporter. Our results suggested that tetrandrine can antagonize MDR in both drug-selected and MDR1 gene-transfected cancer cells by down regulating the expression of the ABCB1 transporter, followed by increasing the intracellular concentration of chemotherapeutic agents. The combinational therapy using tetrandrine and other anticancer drugs could promote the treatment efficiency of drugs that are substrates of ABCB1. View Full-Text
Keywords: ABC transporter; tetrandrine; multidrug resistance (MDR); ABCB1/P-gp; transgenic cancer cell ABC transporter; tetrandrine; multidrug resistance (MDR); ABCB1/P-gp; transgenic cancer cell
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Liao, D.; Zhang, W.; Gupta, P.; Lei, Z.-N.; Wang, J.-Q.; Cai, C.-Y.; Vera, A.A.D.; Zhang, L.; Chen, Z.-S.; Yang, D.-H. Tetrandrine Interaction with ABCB1 Reverses Multidrug Resistance in Cancer Cells Through Competition with Anti-Cancer Drugs Followed by Downregulation of ABCB1 Expression. Molecules 2019, 24, 4383.

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