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Effect of β-elemene on the kinetics of intracellular transport of d-luciferin potassium salt (ABC substrate) in doxorubicin-resistant breast cancer cells and the associated molecular mechanism.
Eur J Pharm Sci. 2018 Jul 30; 120:20-29.EJ

Abstract

In order to explore the mechanism of the reversing multidrug resistance (MDR) phenotypes by β-elemene (β-ELE) in doxorubicin (DOX)-resistant breast cancer cells (MCF-7/DOX), both the functionality and quantity of the ABC transporters in MCF-7/DOX were studied. Bioluminescence imaging (BLI) was used to study the efflux of d-luciferin potassium salt, the substrate of ATP-binding cassette transporters (ABC transporters), in MCF-7/DOX cells treated by β-ELE. At the same time three major ABC transport proteins and genes-related MDR, P-glycoprotein (P-gp, ABCB1) and multidrug resistance-associated protein 1 (MRP, ABCC1) as well as breast cancer resistance protein (BCRP, ABCG2) were analyzed by q-PCR and Western blot. To investigate the efflux functionality of ABC transporters, MCF-7/DOXFluc cell line with stably-overexpressed luciferase was established. BLI was then used to real-time monitor the efflux kinetics of d-luciferin potassium salt before and after MCF-7/DOXFluc cells being treated with β-ELE or not. The results showed that the efflux of d-luciferin potassium salt from MCF-7/DOXFluc was lessened when pretreated with β-ELE, which means that β-ELE may dampen the functionality of ABC transporters, thus decrease the efflux of d-fluorescein potassium or other chemotherapies which also serve as the substrates of ABC transporters. As the effect of β-ELE on the expression of ABC transporters, the results of q-PCR and Western blot showed that gene and protein expression of ABC transporters such as P-gp, MRP, and BCRP were down-regulated after the treatment of β-ELE. To verify the efficacy of β-ELE on reversing MDR, MCF-7/DOX cells were treated with the combination of DOX and β-ELE. MTT assay showed that β-ELE increased the inhibitory effect of DOX on the proliferation of MCF-7/DOX, and the IC50 of the combination group was much lower than that of the single DOX or β-ELE treatment. In all, β-ELE may reverse MDR through the substrates of ABC transporters by two ways, to lessen the ABC protein efflux by weakening their functionality, or to reduce the quantity of ABC gene and protein expression.

Authors+Show Affiliations

College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China; Zhejiang Institute for Food and Drug Control, Hangzhou, Zhejiang 310004, China.College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.Division of Pharmacoengineering and Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill 27599, NC, USA.College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China. Electronic address: xiongyang@zcmu.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29704644

Citation

Tang, Chao-Yuan, et al. "Effect of Β-elemene On the Kinetics of Intracellular Transport of D-luciferin Potassium Salt (ABC Substrate) in Doxorubicin-resistant Breast Cancer Cells and the Associated Molecular Mechanism." European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences, vol. 120, 2018, pp. 20-29.
Tang CY, Zhu LX, Yu JD, et al. Effect of β-elemene on the kinetics of intracellular transport of d-luciferin potassium salt (ABC substrate) in doxorubicin-resistant breast cancer cells and the associated molecular mechanism. Eur J Pharm Sci. 2018;120:20-29.
Tang, C. Y., Zhu, L. X., Yu, J. D., Chen, Z., Gu, M. C., Mu, C. F., Liu, Q., & Xiong, Y. (2018). Effect of β-elemene on the kinetics of intracellular transport of d-luciferin potassium salt (ABC substrate) in doxorubicin-resistant breast cancer cells and the associated molecular mechanism. European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences, 120, 20-29. https://doi.org/10.1016/j.ejps.2018.04.037
Tang CY, et al. Effect of Β-elemene On the Kinetics of Intracellular Transport of D-luciferin Potassium Salt (ABC Substrate) in Doxorubicin-resistant Breast Cancer Cells and the Associated Molecular Mechanism. Eur J Pharm Sci. 2018 Jul 30;120:20-29. PubMed PMID: 29704644.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of β-elemene on the kinetics of intracellular transport of d-luciferin potassium salt (ABC substrate) in doxorubicin-resistant breast cancer cells and the associated molecular mechanism. AU - Tang,Chao-Yuan, AU - Zhu,Li-Xin, AU - Yu,Jian-Dong, AU - Chen,Zhi, AU - Gu,Man-Cang, AU - Mu,Chao-Feng, AU - Liu,Qi, AU - Xiong,Yang, Y1 - 2018/04/25/ PY - 2017/11/22/received PY - 2018/04/06/revised PY - 2018/04/24/accepted PY - 2018/4/29/pubmed PY - 2018/10/16/medline PY - 2018/4/29/entrez KW - Bioluminescence imaging KW - Breast cancer KW - Efflux kinetics KW - Multidrug resistance reverse KW - d-Luciferin potassium salt KW - β-elemene SP - 20 EP - 29 JF - European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences JO - Eur J Pharm Sci VL - 120 N2 - In order to explore the mechanism of the reversing multidrug resistance (MDR) phenotypes by β-elemene (β-ELE) in doxorubicin (DOX)-resistant breast cancer cells (MCF-7/DOX), both the functionality and quantity of the ABC transporters in MCF-7/DOX were studied. Bioluminescence imaging (BLI) was used to study the efflux of d-luciferin potassium salt, the substrate of ATP-binding cassette transporters (ABC transporters), in MCF-7/DOX cells treated by β-ELE. At the same time three major ABC transport proteins and genes-related MDR, P-glycoprotein (P-gp, ABCB1) and multidrug resistance-associated protein 1 (MRP, ABCC1) as well as breast cancer resistance protein (BCRP, ABCG2) were analyzed by q-PCR and Western blot. To investigate the efflux functionality of ABC transporters, MCF-7/DOXFluc cell line with stably-overexpressed luciferase was established. BLI was then used to real-time monitor the efflux kinetics of d-luciferin potassium salt before and after MCF-7/DOXFluc cells being treated with β-ELE or not. The results showed that the efflux of d-luciferin potassium salt from MCF-7/DOXFluc was lessened when pretreated with β-ELE, which means that β-ELE may dampen the functionality of ABC transporters, thus decrease the efflux of d-fluorescein potassium or other chemotherapies which also serve as the substrates of ABC transporters. As the effect of β-ELE on the expression of ABC transporters, the results of q-PCR and Western blot showed that gene and protein expression of ABC transporters such as P-gp, MRP, and BCRP were down-regulated after the treatment of β-ELE. To verify the efficacy of β-ELE on reversing MDR, MCF-7/DOX cells were treated with the combination of DOX and β-ELE. MTT assay showed that β-ELE increased the inhibitory effect of DOX on the proliferation of MCF-7/DOX, and the IC50 of the combination group was much lower than that of the single DOX or β-ELE treatment. In all, β-ELE may reverse MDR through the substrates of ABC transporters by two ways, to lessen the ABC protein efflux by weakening their functionality, or to reduce the quantity of ABC gene and protein expression. SN - 1879-0720 UR - https://www.unboundmedicine.com/medline/citation/29704644/Effect_of_β_elemene_on_the_kinetics_of_intracellular_transport_of_d_luciferin_potassium_salt__ABC_substrate__in_doxorubicin_resistant_breast_cancer_cells_and_the_associated_molecular_mechanism_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0928-0987(18)30202-1 DB - PRIME DP - Unbound Medicine ER -