Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

General Research Article

10-Phenyltriazoyl Artemisinin is a Novel P-glycoprotein Inhibitor that Suppresses the Overexpression and Function of P-glycoprotein

Author(s): Dong-Hwan Lee, Md. Hasanuzzaman, Daeho Kwon, Hye-Young Choi, So Myoung Kim, Dong Jin Kim, Dong Ju Kang, Tae-Ho Hwang, Hyung-Hoi Kim, Ho Jung Shin, Jae-Gook Shin, Sangtae Oh, Seokjoon Lee* and So Won Kim*

Volume 24 , Issue 46 , 2018

Page: [5590 - 5597] Pages: 8

DOI: 10.2174/1381612825666190222155700

Price: $65


Background: The effect of drugs on ATP-binding cassette transporters, especially permeabilityglycoprotein (P-gp), is an important consideration during new anti-cancer drug development.

Objective: In this context, the effects of a newly synthesized artemisinin derivative, 10-(4-phenyl-1H-1,2,3- triazol)-artemisinin (5a), were evaluated on P-gp expression and function.

Methods: Reverse transcript polymerase chain reaction and immunoblotting techniques were used to determine the effect of 5a on P-gp expression in LS174T cells. In addition, the ability of 5a to work as either a substrate or an inhibitor of P-gp was investigated through different methods.

Results: The results revealed that 5a acts as a novel P-gp inhibitor that dually suppresses the overexpression and function of P-glycoprotein. Co-treatment of LS174T cell line, human colon adenocarcinoma cell line, with 5a and paclitaxel recovered the anticancer effect of paclitaxel by controlling the acquired drug resistance pathway. The overexpression of P-gp induced by rifampin and paclitaxel in a colorectal cell line was suppressed by 5a which could be a novel inhibitory substrate inhibiting the transport of paclitaxel by P-gp.

Conclusion: The results revealed that 5a can be classified as a type B P-gp inhibitor (with both substrate and inhibitor activities) with an additional function of suppressing P-gp overexpression. The results might be clinically useful in the development of anticancer drugs against cancers with multidrug resistance.

Keywords: Artemisinin, triazolyl artemisinin, p-glycoprotein, rifampin, paclitaxel, immunoblotting techniques.

Hard to swallow. Nature 2007; 448(7150): 105-6.
Klayman DL. Qinghaosu (artemisinin): an antimalarial drug from China. Science 1985; 228(4703): 1049-55.
Lee S. Artemisinin, promising lead natural product for various drug developments. Mini Rev Med Chem 2007; 7(4): 411-22.
Oh S, Jeong IH, Shin WS, Lee S. Growth inhibition activity of thioacetal artemisinin derivatives against human umbilical vein endothelial cells. Bioorg Med Chem Lett 2003; 13(21): 3665-8.
Oh S, Jeong IH, Ahn CM, Shin WS, Lee S. Synthesis and antiangiogenic activity of thioacetal artemisinin derivatives. Bioorg Med Chem 2004; 12(14): 3783-90.
Oh S, Shin WS, Ham J, Lee S. Synthesis of Artemisinins with Substituted Sulfidyl or Sulfonyl Moiety and Their Anti-angiogenesis Activity. Bull Korean Chem Soc 2011; 32(8): 2823-6.
Lai HC, Singh NP, Sasaki T. Development of artemisinin compounds for cancer treatment. Invest New Drugs 2013; 31(1): 230-46.
Cho S, Oh S, Um Y, et al. Synthesis of 10-substituted triazolyl artemisinins possessing anticancer activity via Huisgen 1,3-dipolar cylcoaddition. Bioorg Med Chem Lett 2009; 19(2): 382-5.
Oh S, Shin WS, Ham J, Lee S. Acid-catalyzed synthesis of 10-substituted triazolyl artemisinins and their growth inhibitory activity against various cancer cells. Bioorg Med Chem Lett 2010; 20(14): 4112-5.
Lee S. Synthesis of 10β-Substituted Triazolyl Artemisinins and Their Growth Inhibitory Activity against Various Cancer Cells. Bull Korean Chem Soc 2011; 32(2): 737-40.
Ikeda M, Kaneko M, Tachibana SI, et al. Artemisinin-Resistant Plasmodium falciparum with High Survival Rates, Uganda, 2014-2016. Infect Dis 2018; 24(4): 718-26.
Guan WB, Huang HJ, Zhou YC, Gong JZ. Effect in vitro of artemisinine and its derivatives on Plasmodium falciparum. Zhongguo Yao Li Xue Bao 1982; 3(2): 139-41.
Lisa Gruber L, Abdelfatah S, Fröhlich T, et al. Treatment of Multidrug-Resistant Leukemia Cells by Novel Artemisinin-, Egonol-, and Thymoquinone-Derived Hybrid Compounds. Molecules 2018; 23(4): E841.
Das AK. Anticancer Effect of AntiMalarial Artemisinin Compounds. Ann Med Health Sci Res 2015; 5(2): 93-102.
Efferth T, Sauerbrey A, Olbrich A, et al. Molecular modes of action of artesunate in tumor cell lines. Mol Pharmacol 2003; 64(2): 382-94.
Reungpatthanaphong P, Mankhetkorn S. Modulation of multidrug resistance by artemisinin, artesunate and dihydroartemisinin in K562/adr and GLC4/adr resistant cell lines. Biol Pharm Bull 2002; 25(12): 1555-61.
Gervasini G, Carrillo JA, Garcia M, San Jose C, Cabanillas A, Benitez J. Adenosine triphosphate-binding cassette B1 (ABCB1) (multidrug resistance 1) G2677T/A gene polymorphism is associated with high risk of lung cancer. Cancer 2006; 107(12): 2850-7.
Miller DS, Bauer B, Hartz AM. Modulation of P-glycoprotein at the blood-brain barrier: opportunities to improve central nervous system pharmacotherapy. Pharmacol Rev 2008; 60(2): 196-209.
Zhou SF. Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition. Xenobiotica 2008; 38(7-8): 802-32.
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.
Gottesman MM. Mechanisms of cancer drug resistance. Annu Rev Med 2002; 53: 615-27.
Falasca M, Linton KJ. Investigational ABC transporter inhibitors. Expert Opin Investig Drugs 2012; 21(5): 657-66.
Dong X, Mumper RJ. Nanomedicinal strategies to treat multidrug-resistant tumors: current progress. Nanomedicine (Lond) 2010; 5(4): 597-615.
Szakacs G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM. Targeting multidrug resistance in cancer. Nat Rev Drug Discov 2006; 5(3): 219-34.
Ettlin RA, Kuroda J, Plassmann S, Hayashi M, Prentice DEJ. Successful drug development despite adverse preclinical findings part 2: examples. Toxicol Pathol 2010; 23(4): 213-34.
Kwak JO, Lee SH, Lee GS, et al. Elective inhibition of MDR1 (ABCB1) by HM30181 increases oral bioavailability and therapeutic efficacy of paclitaxel. Eur J Pharmacol 2010; 627(1-3): 92-8.
von Richter O, Glavinas H, Krajcsi P, Liehner S, Siewert B, Zech K. A novel screening strategy to identify ABCB1 substrates and inhibitors. Naunyn Schmiedebergs Arch Pharmacol 2009; 379(1): 11-26.
Kim SW, Md H, Cho M, et al. Casein Kinase 2 (CK2)-mediated Phosphorylation of Hsp90β as a Novel Mechanism of Rifampin-induced MDR1 Expression. J Biol Chem 2015; 290(27): 17029-40.
Kim SW, Md H, Cho M, et al. Role of 14-3-3 sigma in over-expression of P-gp by rifampin and paclitaxel stimulation through interaction with PXR. Cell Signal 2017; 31: 124-34.
Ertl P, Roggo S, Schuffenhauer AJ. Natural product-likeness score and its application for prioritization of compound libraries. Chem Inf Model 2008; 48(1): 68-74.
Prachayasittikul V, Prachayasittikul V. P-glycoprotein transporter in drug development. EXCLI J 2016; 15: 113-8.
Nanayakkara AK, Follit CA, Chen G, Williams NS, Vogel PD, Wise JG. Targeted inhibitors of P-glycoprotein increase chemotherapeutic-induced mortality of multidrug resistant tumor cells. Sci Rep 2018; 8(1): 967.
Bentires-Alj M, Barbu V, Fillet M, et al. NF-kappaB transcription factor induces drug resistance through MDR1 expression in cancer cells. Oncogene 2003; 22(1): 90-7.
Xi G, Hayes E, Lewis R, et al. CD133 and DNA-PK regulate MDR1 via the PI3K- or Akt-NF-κB pathway in multidrug-resistant glioblastoma cells in vitro. Oncogene 2016; 35(42): 5576.
Katayama K, Noguchi K, Sugimoto Y. Regulations of PGlycoprotein/ABCB1/MDR1 in Human Cancer Cells. New J Sci In: 2014. Article ID 476974, 10 pages.
Sukhai M, Piquette-Miller MJ. Regulation of the multidrug resistance genes by stress signals. Pharm Pharm Sci 2000; 3(2): 268-80.
Andorfer P, Rotheneder H. Regulation of the MDR1 promoter by E2F1 and EAPP. FEBS Lett 2013; 587(10): 1504-9.
Vilaboa NE, Galán A, Troyano A, de Blas E, Aller PJ. Regulation of multidrug resistance 1 (MDR1)/P-glycoprotein gene expression and activity by heat-shock transcription factor 1 (HSF1). J Biol Chem 2000; 275(32): 24970-6.
Zhao Y, Liu J, Hong Q, et al. Involvement of MyoD and PEA3 in regulation of transcription activity of MDR1 gene. Acta Biochim Biophys Sin (Shanghai) 2010; 42(12): 900-7.
Okamura H, Yoshida K, Sasaki E, Morimoto H, Haneji T. Transcription factor NF-Y regulates mdr1 expression through binding to inverted CCAAT sequence in drug-resistant human squamous carcinoma cells. Int J Oncol 2004; 25(4): 1031-7.
Gromnicova R, Romero I, Male D. Transcriptional control of the multi-drug transporter ABCB1 by transcription factor Sp3 in different human tissues. PLoS One 2012; 7(10): e48189.

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy