Issue

Vol. 65 No. 1: Issue 1

The undersigned hereby assign all rights, included but not limited to copyright, for this manuscript to CMB Association upon its submission for consideration to publication on Cellular and Molecular Biology. The rights assigned include, but are not limited to, the sole and exclusive rights to license, sell, subsequently assign, derive, distribute, display and reproduce this manuscript, in whole or in part, in any format, electronic or otherwise, including those in existence at the time this agreement was signed. The authors hereby warrant that they have not granted or assigned, and shall not grant or assign, the aforementioned rights to any other person, firm, organization, or other entity. All rights are automatically restored to authors if this manuscript is not accepted for publication.

Schizandrol A reverses multidrug resistance in resistant chronic myeloid leukemia cells K562/A02

https://doi.org/10.14715/cmb/2019.65.1.14
Nurguli Arken

Corresponding Author(s) : Nurguli Arken

jg90927@163.com

Cellular and Molecular Biology, Vol. 65 No. 1: Issue 1

Abstract

Overexpression of P-gp is the main cause of multidrug resistance (MDR) and chemotherapeutic failure in leukemia. In this study, the multidrug resistance reverse effect of Schizandrol A (SchA) was demonstrated with P-gp overexpressed drug-resistant K562/A02 cells. SchA had almost no cytotoxic activity, the EC50 value reversed to DOX was in the nanomole range of (707 ± 29nM) and had a high selectivity index (> 113) to normal cells. DOX accumulation and Rh123 efflux tests demonstrated that the MDR reversal activity of SchA was induced by inhibiting P-gp function. Western blotting assay showed that SchA down-regulated the expression of P-gp by inhibiting the PI3K / Akt signaling pathway, which was also a key factor in reversal activity. Therefore, SchA may be a potential candidate for natural MDR reversal agents.

Keywords

Multidrug resistance P-gp Chronic myeloid leukemia Schizandrol A Reversal activity.
Arken, N. (2019). Schizandrol A reverses multidrug resistance in resistant chronic myeloid leukemia cells K562/A02. Cellular and Molecular Biology, 65(1), 78–83. https://doi.org/10.14715/cmb/2019.65.1.14
Download Citation
Endnote/Zotero/Mendeley (RIS)
BibTeX
References
  1. Cao R, Wang Y, Huang N. Discovery of 2-Acylaminothiophene-3-Carboxamides as Multitarget Inhibitors for BCR-ABL Kinase and Microtubules. J Chem Inf Model 2015; 55: 2435.
  2. Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2016 update on diagnosis, therapy, and monitoring. Am J Hematol 2016; 91: 252-265.
  3. Rebucci M, Michiels C. Molecular aspects of cancer cell resistance to chemotherapy. Biochem Pharmacol 2013; 85: 1219-1226.
  4. Gottesman MM. Mechanisms of cancer drug resistance. Annual Rev Med 2002; 53: 615-627.
  5. Szakács G, Paterson JK, Ludwig JA, Boothgenthe C, Gottesman MM. Targeting multidrug resistance in cancer. Nat Rev Drug Discovery 2006; 5: 219-234.
  6. Krishna R, Mayer LD. Multidrug resistance (MDR) in cancer. Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. Eur J Pharm Sci 2000; 11: 265-283.
  7. Gillet J, Gottesman MM. Mechanisms of Multidrug Resistance in Cancer. Methods Mol Biol 2010; 596: 47-76.
  8. Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP|[ndash]|dependent transporters. Nat Rev Cancer 2002; 2: 48-58.
  9. Borowski E, Bontemps-Gracz MM, Piwkowska A. Strategies for overcoming ABC-transporters-mediated multidrug resistance (MDR) of tumor cells. Acta Biochimica Polonica 2005; 52: 609.
  10. Marchetti S, Mazzanti R, Beijnen JH, Schellens JHM. Concise Review: Clinical Relevance of Drug–Drug and Herb–Drug Interactions Mediated by the ABC Transporter ABCB1 (MDR1, P-glycoprotein). Oncologist 2007; 12: 927-941.
  11. Ford RC, Kamis AB, Kerr ID, Callaghan R. The ABC Transporters: Structural Insights into Drug Transport. Wiley"VCH Verlag GmbH & Co. KGaA; 2010.
  12. Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci U S A 1987; 84: 7735-7738.
  13. Dawson RJP, Locher KP. Structure of a bacterial multidrug ABC transporter. Nat 2006; 443: 180-185.
  14. Wu CP, Hsieh CH, Wu YS. The Emergence of Drug Transporter-Mediated Multidrug Resistance to Cancer Chemotherapy. Mol Pharm 2011; 8: 1996-2011.
  15. SG A, J Y, A W, et al. Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Sci 2009; 323: 1718-1722.
  16. Guo M, An F, Wei X, Hong M, Lu Y. Comparative Effects of Schisandrin A, B, and C on Acne-Related Inflammation. Inflamm 2017; 40: 1-10.
  17. Guo LY, Hung TM, Bae KH, Shin EM, Zhou HY, Hong YN, et al. Anti-inflammatory effects of schisandrin isolated from the fruit of Schisandra chinensis Baill. Eur J Pharmacol 2008; 591: 293-299.
  18. Nishida H, Tatewaki N, Nakajima Y, Magara T, Ko KM, Hamamori Y, et al. Inhibition of ATR protein kinase activity by schisandrin B in DNA damage response. Nucleic Acids Res 2009; 37: 5678-5689.
  19. Ip SP, Poon MKT, Wu SS, Che CT, Ng KH, Kong YC, et al. Effect of Schisandrin B on Hepatic Glutathione Antioxidant System in Mice: Protection against Carbon Tetrachloride Toxicity. Planta Med 1995; 61: 398-401.
  20. Huang T, Shen P, Shen Y. Preparative separation and purification of deoxyschisandrin and gamma-schisandrin from Schisandra chinensis (Turcz.) Baill by high-speed counter-current chromatography. J Chromatography A 2005; 1066: 239-242.
  21. Qiu Q, Wei S, Zheng L, Zhang B, Pan M, Cui J, et al. Exploration of 2-((pyridin-4-ylmethyl) amino)nicotinamide derivatives as potent reversal agents against P-glycoprotein-mediated multidrug resistance. J Med Chem 2017; 60: 2930-2943.
  22. Chan K-F, Wong IL, Kan JW, Yan CS, Chow LM, Chan TH. Amine Linked Flavonoid Dimers as Modulators for P-Glycoprotein-Based Multidrug Resistance: Structure–Activity Relationship and Mechanism of Modulation. J Med Chem 2012; 55: 1999-2014.
  23. Perche F, Torchilin VP. Accumulation and toxicity of antibody-targeted doxorubicin-loaded PEG-PE micelles in ovarian cancer cell spheroid model. J Controlled Release 2012; 164: 95-102.
  24. Ji BS, He L. CJY, an isoflavone, reverses P-glycoprotein-mediated multidrug-resistance in doxorubicin-resistant human myelogenous leukaemia (K562/DOX) cells. J Pharm Pharmacol 2010; 59: 1011-1015.
  25. Callaghan R, George AM, Kerr ID. 8.8 Molecular Aspects of the Translocation Process by ABC Proteins. Compr Biophys 2012: 145-173.
  26. Stouch TR, Gudmundsson O. Progress in understanding the structure–activity relationships of P-glycoprotein. Advanced Drug Delivery Rev 2002; 54(3):315-328.
  27. And YR, Sharom FJ. The Membrane Lipid Environment Modulates Drug Interactions with the P-Glycoprotein Multidrug Transporter. Biochem 1999; 38: 6887.
  28. Robert J, Jarry C. Multidrug resistance reversal agents. Cheminform 2004; 35: 4805-4817.
  29. Ireland C, Aalbersberg W, Andersen R. Anticancer Agents from Unique Natural Products Sources. Pharm Biol 2003; 41: 15-38.
  30. Dewanjee S, Dua TK, Bhattacharjee N, Das A, Gangopadhyay M, Khanra R, et al. Natural Products as Alternative Choices for P-Glycoprotein (P-gp) Inhibition. Molecules 2017; 22.
  31. Li H, Hui L, Xu W, Shen H, Chen Q, Long L, et al. Modulation of P-glycoprotein expression by triptolide in adriamycin-resistant K562/A02 cells. Oncol Lett 2012; 3: 485-489.
  32. Mathisen MS, Kantarjian HM, Cortes J, Jabbour E. Mutant BCR-ABL clones in chronic myeloid leukemia. Haematologica 2011; 96: 347.
  33. Ma H, Cheng L, Hao K, Li Y, Song X, Zhou H, et al. Reversal Effect of ST6GAL 1 on Multidrug Resistance in Human Leukemia by Regulating the PI3K/Akt Pathway and the Expression of P-gp and MRP1. PloS one 2014; 9: 85113.
Read More
Author biographies is not available.
Crossref
Scopus
Google Scholar
Europe PMC
Download this PDF file
PDF
Statistic
Read Counter : 780 Download : 432