Clerosterol from Vinegar-baked Radix Bupleuri Modifies Drug Transport

Overview

Journal Oncotarget

Specialty Oncology

Date 2017 Apr 21

PMID 28423482

Citations 2

Authors

Ya Zhao

Li-Min Feng

Li-Juan Liu

Xian Zhang

Rui-Zhi Zhao

Affiliations

Soon will be listed here.

Abstract

Vinegar-baked Radix Bupleuri (VBRB) is reportedly used to treat liver cancer when combined with traditional chemotherapy and data show that this combination may modify drug transport. We isolated clerosterol from VBRB and studied its effect on drug transporters in normal or transporter-overexpressing cells. Transporter activity was assayed using cellular substrate concentration and transporter expression with Western blot and RT-qPCR. Clerosterol decreased cisplatin uptake in BRL cells mainly through increasing Mrp2 gene expression. Clerosterol also decreased the uptake of colchicine in HEK 293 cells by increasing both Pgp and Mrp1 activity; in detail, it could increase Pgp protein but had marginal effects on Mrp1 protein and gene expression. Further study showed clerosterol increased OCT2 activity in HEK293-Pgp cells by increasing OCT2 protein and mRNA. Clerosterol could suppress Pgp overexpression but not by regulating protein and gene expression. And clerosterol had marginal effects on Mrp2 and Mrp1 activity in Mrp2- and Mrp1-overexpressing HEK293 cells. Thus, Clerosterol may be an active constituent of VBRB and may work against cancer multidrug resistance by inhibiting Pgp activity.

Citing Articles

Saikosaponin b2 enhances the hepatotargeting effect of anticancer drugs through inhibition of multidrug resistance-associated drug transporters.

Zhao Y, Feng L, Liu L, Zhao R Life Sci. 2019; 231:116557.

PMID: 31194994 PMC: 7094655. DOI: 10.1016/j.lfs.2019.116557.

Saikosaponins A, C and D enhance liver-targeting effects of anticancer drugs by modulating drug transporters.

Feng L, Liu L, Zhao Y, Zhao R Oncotarget. 2018; 8(66):110092-110102.

PMID: 29299132 PMC: 5746367. DOI: 10.18632/oncotarget.22639.

References

Wong V, Zhang M, Zhou H, Ching Lam K, Chan P, Law C . Saikosaponin-d Enhances the Anticancer Potency of TNF-α via Overcoming Its Undesirable Response of Activating NF-Kappa B Signalling in Cancer Cells. Evid Based Complement Alternat Med. 2013; 2013:745295. PMC: 3610377. DOI: 10.1155/2013/745295. View

Szakacs G, Varadi A, Ozvegy-Laczka C, Sarkadi B . The role of ABC transporters in drug absorption, distribution, metabolism, excretion and toxicity (ADME-Tox). Drug Discov Today. 2008; 13(9-10):379-93. DOI: 10.1016/j.drudis.2007.12.010. View

Ciarimboli G, Deuster D, Knief A, Sperling M, Holtkamp M, Edemir B . Organic cation transporter 2 mediates cisplatin-induced oto- and nephrotoxicity and is a target for protective interventions. Am J Pathol. 2010; 176(3):1169-80. PMC: 2832140. DOI: 10.2353/ajpath.2010.090610. View

Zhang Y, Wang Y, Gupta P, Chen Z . Multidrug Resistance Proteins (MRPs) and Cancer Therapy. AAPS J. 2015; 17(4):802-12. PMC: 4476997. DOI: 10.1208/s12248-015-9757-1. View

Lu X, He S, Ren M, Wang Y, Zhang Y, Liu E . Chemopreventive effect of saikosaponin-d on diethylinitrosamine-induced hepatocarcinogenesis: involvement of CCAAT/enhancer binding protein β and cyclooxygenase-2. Mol Med Rep. 2011; 5(3):637-44. DOI: 10.3892/mmr.2011.702. View

Kulik L, Chokechanachaisakul A . Evaluation and management of hepatocellular carcinoma. Clin Liver Dis. 2014; 19(1):23-43. DOI: 10.1016/j.cld.2014.09.002. View

Ciarimboli G . Membrane transporters as mediators of cisplatin side-effects. Anticancer Res. 2014; 34(1):547-50. View

Zhao R, Liu L, Wang Y, Xiao Z . Vinegar-baked Radix Bupleuri modulates the cell membrane constituents and inhibits the P-gp activity in rat hepatocytes. BMC Complement Altern Med. 2014; 14:357. PMC: 4192444. DOI: 10.1186/1472-6882-14-357. View

Chen Z, Chen Y, Xu M, Chen L, Zhang X, To K . Osimertinib (AZD9291) Enhanced the Efficacy of Chemotherapeutic Agents in ABCB1- and ABCG2-Overexpressing Cells In Vitro, In Vivo, and Ex Vivo. Mol Cancer Ther. 2016; 15(8):1845-58. DOI: 10.1158/1535-7163.MCT-15-0939. View

10.

Kwon H, Min Y, Kim K, Bang E, Lee C, Lee K . A new acylglycosyl sterol from Quisqualis Fructus. Arch Pharm Res. 2003; 26(4):275-8. DOI: 10.1007/BF02976955. View

11.

Dlugosz A, Janecka A . ABC Transporters in the Development of Multidrug Resistance in Cancer Therapy. Curr Pharm Des. 2016; 22(30):4705-4716. DOI: 10.2174/1381612822666160302103646. View

12.

DeGorter M, Xia C, Yang J, Kim R . Drug transporters in drug efficacy and toxicity. Annu Rev Pharmacol Toxicol. 2011; 52:249-73. DOI: 10.1146/annurev-pharmtox-010611-134529. View

13.

Dury L, Nasr R, Lorendeau D, Comsa E, Wong I, Zhu X . Flavonoid dimers are highly potent killers of multidrug resistant cancer cells overexpressing MRP1. Biochem Pharmacol. 2016; 124:10-18. DOI: 10.1016/j.bcp.2016.10.013. View

14.

Schinkel A, Jonker J . Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. Adv Drug Deliv Rev. 2003; 55(1):3-29. DOI: 10.1016/s0169-409x(02)00169-2. View

15.

Filipski K, Mathijssen R, Mikkelsen T, Schinkel A, Sparreboom A . Contribution of organic cation transporter 2 (OCT2) to cisplatin-induced nephrotoxicity. Clin Pharmacol Ther. 2009; 86(4):396-402. PMC: 2746866. DOI: 10.1038/clpt.2009.139. View

16.

Bachran C, Bachran S, Sutherland M, Bachran D, Fuchs H . Saponins in tumor therapy. Mini Rev Med Chem. 2008; 8(6):575-84. DOI: 10.2174/138955708784534445. View

17.

Wu T, Chen Z, To K, Fang X, Wang F, Cheng B . Effect of abemaciclib (LY2835219) on enhancement of chemotherapeutic agents in ABCB1 and ABCG2 overexpressing cells in vitro and in vivo. Biochem Pharmacol. 2016; 124:29-42. DOI: 10.1016/j.bcp.2016.10.015. View

18.

Renes J, De Vries E, Nienhuis E, Jansen P, Muller M . ATP- and glutathione-dependent transport of chemotherapeutic drugs by the multidrug resistance protein MRP1. Br J Pharmacol. 1999; 126(3):681-8. PMC: 1565864. DOI: 10.1038/sj.bjp.0702360. View

19.

Sprowl J, Lancaster C, Pabla N, Hermann E, Kosloske A, Gibson A . Cisplatin-induced renal injury is independently mediated by OCT2 and p53. Clin Cancer Res. 2014; 20(15):4026-35. PMC: 4119572. DOI: 10.1158/1078-0432.CCR-14-0319. View