Skip to main content

Advertisement

SpringerLink
Log in

Resistance to the Translation Initiation Inhibitor Silvestrol is Mediated by ABCB1/P-Glycoprotein Overexpression in Acute Lymphoblastic Leukemia Cells

  • Research Paper
  • Published:
The AAPS Journal Aims and scope Submit manuscript

Abstract

Protein synthesis is a powerful therapeutic target in leukemias and other cancers, but few pharmacologically viable agents are available that affect this process directly. The plant-derived agent silvestrol specifically inhibits translation initiation by interfering with eIF4A/mRNA assembly with eIF4F. Silvestrol has potent in vitro and in vivo activity in multiple cancer models including acute lymphoblastic leukemia (ALL) and is under pre-clinical development by the US National Cancer Institute, but no information is available about potential mechanisms of resistance. In a separate report, we showed that intraperitoneal silvestrol is approximately 100% bioavailable systemically, although oral doses were only 1% bioavailable despite an apparent lack of metabolism. To explore mechanisms of silvestrol resistance and the possible role of efflux transporters in silvestrol disposition, we characterized multi-drug resistance transporter expression and function in a silvestrol-resistant ALL cell line generated via culture of the 697 ALL cell line in gradually increasing silvestrol concentrations. This resistant cell line, 697-R, shows significant upregulation of ABCB1 mRNA and P-glycoprotein (Pgp) as well as cross-resistance to known Pgp substrates vincristine and romidepsin. Furthermore, 697-R cells readily efflux the fluorescent Pgp substrate rhodamine 123. This effect is prevented by Pgp inhibitors verapamil and cyclosporin A, as well as siRNA to ABCB1, with concomitant re-sensitization to silvestrol. Together, these data indicate that silvestrol is a substrate of Pgp, a potential obstacle that must be considered in the development of silvestrol for oral delivery or targeting to tumors protected by Pgp overexpression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

REFERENCES

  1. Lazaris-Karatzas A, Montine KS, Sonenberg N. Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5′ cap. Nature. 1990;345(6275):544–7.

    Article  PubMed  CAS  Google Scholar 

  2. Rosenwald IB, Chen JJ, Wang S, Savas L, London IM, Pullman J. Upregulation of protein synthesis initiation factor eIF-4E is an early event during colon carcinogenesis. Oncogene. 1999;18(15):2507–17.

    Article  PubMed  CAS  Google Scholar 

  3. Zimmer SG, DeBenedetti A, Graff JR. Translational control of malignancy: the mRNA cap-binding protein, eIF-4E, as a central regulator of tumor formation, growth, invasion and metastasis. Anticancer Res. 2000;20(3A):1343–51.

    PubMed  CAS  Google Scholar 

  4. Lane HA, Breuleux M. Optimal targeting of the mTORC1 kinase in human cancer. Curr Opin Cell Biol. 2009;21(2):219–29.

    Article  PubMed  CAS  Google Scholar 

  5. Meric F, Hunt KK. Translation initiation in cancer: a novel target for therapy. Mol Cancer Ther. 2002;1(11):971–9.

    PubMed  CAS  Google Scholar 

  6. Dowling RJ, Topisirovic I, Fonseca BD, Sonenberg N. Dissecting the role of mTOR: lessons from mTOR inhibitors. Biochim Biophys Acta. 2009;1804(3):433–9.

    PubMed  Google Scholar 

  7. Robert F, Pelletier J. Translation initiation: a critical signalling node in cancer. Expert Opin Ther Targets. 2009;13(11):1279–93.

    Article  PubMed  CAS  Google Scholar 

  8. Hwang BY, Su BN, Chai H, Mi Q, Kardono LB, Afriastini JJ, et al. Silvestrol and episilvestrol, potential anticancer rocaglate derivatives from Aglaia silvestris. J Org Chem. 2004;69(10):3350–8. ibid. 6156.

    Article  PubMed  CAS  Google Scholar 

  9. Kim S, Hwang BY, Su BN, Chai H, Mi Q, Kinghorn AD, et al. Silvestrol, a potential anticancer rocaglate derivative from Aglaia foveolata, induces apoptosis in LNCaP cells through the mitochondrial/apoptosome pathway without activation of executioner caspase-3 or -7. Anticancer Res. 2007;27(4B):2175–83.

    PubMed  CAS  Google Scholar 

  10. Lucas DM, Edwards RB, Lozanski G, West DA, Shin JD, Vargo MA, et al. The novel plant-derived agent silvestrol has B-cell selective activity in chronic lymphocytic leukemia and acute lymphoblastic leukemia in vitro and in vivo. Blood. 2009;113(19):4656–66.

    Article  PubMed  CAS  Google Scholar 

  11. Bordeleau ME, Robert F, Gerard B, Lindqvist L, Chen SM, Wendel HG, et al. Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma model. J Clin Invest. 2008;118:1–11.

    Article  Google Scholar 

  12. Cencic R, Carrier M, Galicia-Vazquez G, Bordeleau ME, Sukarieh R, Bourdeau A, et al. Antitumor activity and mechanism of action of the cyclopenta[b]benzofuran, silvestrol. PLoS ONE. 2009;4(4):e5223.

    Article  PubMed  Google Scholar 

  13. Cencic R, Carrier M, Trnkus A, Porco Jr JA, Minden M, Pelletier J. Synergistic effect of inhibiting translation initiation in combination with cytotoxic agents in acute myelogenous leukemia cells. Leuk Res. 2010;34(4):535–41.

    Article  PubMed  CAS  Google Scholar 

  14. Swerts K, De Moerloose B, Dhooge C, Laureys G, Benoit Y, Philippe J. Prognostic significance of multidrug resistance-related proteins in childhood acute lymphoblastic leukaemia. Eur J Cancer. 2006;42(3):295–309.

    Article  PubMed  CAS  Google Scholar 

  15. Murakami T, Takano M. Intestinal efflux transporters and drug absorption. Expert Opin Drug Metab Toxicol. 2008;4(7):923–39.

    Article  PubMed  CAS  Google Scholar 

  16. Findley Jr HW, Cooper MD, Kim TH, Alvarado C, Ragab AH. Two new acute lymphoblastic leukemia cell lines with early B-cell phenotypes. Blood. 1982;60(6):1305–9.

    PubMed  Google Scholar 

  17. Perkins C, Kim CN, Fang G, Bhalla KN. Arsenic induces apoptosis of multidrug-resistant human myeloid leukemia cells that express Bcr-Abl or overexpress MDR, MRP, Bcl-2, or Bcl-x(L). Blood. 2000;95(3):1014–22.

    PubMed  CAS  Google Scholar 

  18. Aron JL, Parthun MR, Marcucci G, Kitada S, Mone AP, Davis ME, et al. Depsipeptide (FR901228) induces histone acetylation and inhibition of histone deacetylase in chronic lymphocytic leukemia cells concurrent with activation of caspase 8-mediated apoptosis and down-regulation of c-FLIP protein. Blood. 2003;102(2):652–8.

    Article  PubMed  CAS  Google Scholar 

  19. Maynadie M, Matutes E, Catovsky D. Quantification of P-glycoprotein in chronic lymphocytic leukemia by flow cytometry. Leuk Res. 1997;21(9):825–31.

    Article  PubMed  CAS  Google Scholar 

  20. Ghetie MA, Ghetie V, Vitetta ES. Anti-CD19 antibodies inhibit the function of the P-gp pump in multidrug-resistant B lymphoma cells. Clin Cancer Res. 1999;5(12):3920–7.

    PubMed  CAS  Google Scholar 

  21. Hussain SR, Cheney CM, Johnson AJ, Lin TS, Grever MR, Caligiuri MA, et al. Mcl-1 is a relevant therapeutic target in acute and chronic lymphoid malignancies: down-regulation enhances rituximab-mediated apoptosis and complement-dependent cytotoxicity. Clin Cancer Res. 2007;13(7):2144–50.

    Article  PubMed  CAS  Google Scholar 

  22. Khinkis LA, Levasseur L, Faessel H, Greco WR. Optimal design for estimating parameters of the 4-parameter hill model. Nonlinearity Biol Toxicol Med. 2003;1(3):363–77.

    Article  PubMed  CAS  Google Scholar 

  23. Horio M, Gottesman MM, Pastan I. ATP-dependent transport of vinblastine in vesicles from human multidrug-resistant cells. Proc Natl Acad Sci USA. 1988;85(10):3580–4.

    Article  PubMed  CAS  Google Scholar 

  24. Xiao JJ, Foraker AB, Swaan PW, Liu S, Huang Y, Dai Z, et al. Efflux of depsipeptide FK228 (FR901228, NSC-630176) is mediated by P-glycoprotein and multidrug resistance-associated protein 1. J Pharmacol Exp Ther. 2005;313(1):268–76.

    Article  PubMed  CAS  Google Scholar 

  25. Xiao JJ, Huang Y, Dai Z, Sadee W, Chen J, Liu S, et al. Chemoresistance to depsipeptide FK228 [(E)-(1S,4S,10S,21R)-7-[(Z)-ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithi a-5,8,20,23-tetraazabicyclo(6–8)-tricos-16-ene-3,6,9,22-pentanone] is mediated by reversible MDR1 induction in human cancer cell lines. J Pharmacol Exp Ther. 2005;314(1):467–75.

    Article  PubMed  CAS  Google Scholar 

  26. Mi Q, Kim S, Hwang BY, Su BN, Chai H, Arbieva ZH, et al. Silvestrol regulates G2/M checkpoint genes independent of p53 activity. Anticancer Res. 2006;26(5A):3349–56.

    PubMed  CAS  Google Scholar 

  27. Lee JS, Paull K, Alvarez M, Hose C, Monks A, Grever M, et al. Rhodamine efflux patterns predict P-glycoprotein substrates in the National Cancer Institute drug screen. Mol Pharmacol. 1994;46(4):627–38.

    PubMed  CAS  Google Scholar 

  28. Alvarez M, Paull K, Monks A, Hose C, Lee JS, Weinstein J, et al. Generation of a drug resistance profile by quantitation of mdr-1/P-glycoprotein in the cell lines of the National Cancer Institute Anticancer Drug Screen. J Clin Invest. 1995;95(5):2205–14.

    Article  PubMed  CAS  Google Scholar 

  29. Callen DF, Baker E, Simmers RN, Seshadri R, Roninson IB. Localization of the human multiple drug resistance gene, MDR1, to 7q21.1. Hum Genet. 1987;77(2):142–4.

    Article  PubMed  CAS  Google Scholar 

  30. Wartenberg M, Fischer K, Hescheler J, Sauer H. Redox regulation of P-glycoprotein-mediated multidrug resistance in multicellular prostate tumor spheroids. Int J Cancer. 2000;85(2):267–74.

    PubMed  CAS  Google Scholar 

  31. Nwaozuzu OM, Sellers LA, Barrand MA. Signalling pathways influencing basal and H(2)O(2)-induced P-glycoprotein expression in endothelial cells derived from the blood–brain barrier. J Neurochem. 2003;87(4):1043–51.

    Article  PubMed  CAS  Google Scholar 

  32. Thevenod F, Friedmann JM, Katsen AD, Hauser IA. Up-regulation of multidrug resistance P-glycoprotein via nuclear factor-kappaB activation protects kidney proximal tubule cells from cadmium- and reactive oxygen species-induced apoptosis. J Biol Chem. 2000;275(3):1887–96.

    Article  PubMed  CAS  Google Scholar 

  33. Wartenberg M, Fischer K, Hescheler J, Sauer H. Modulation of intrinsic P-glycoprotein expression in multicellular prostate tumor spheroids by cell cycle inhibitors. Biochim Biophys Acta. 2002;1589(1):49–62.

    Article  PubMed  CAS  Google Scholar 

  34. Baker EK, El-Osta A. MDR1, chemotherapy and chromatin remodeling. Cancer Biol Ther. 2004;3(9):819–24.

    Article  PubMed  CAS  Google Scholar 

  35. Kantharidis P, El-Osta A, deSilva M, Wall DM, Hu XF, Slater A, et al. Altered methylation of the human MDR1 promoter is associated with acquired multidrug resistance. Clin Cancer Res. 1997;3(11):2025–32.

    PubMed  CAS  Google Scholar 

Download references

ACKNOWLEDGMENTS

The authors thank Dr. Kapil Bhalla (University of Kansas Cancer Center), for providing the ABCB1-overexpressing HL60 cell line, and Dr. Charles Morrow (Wake Forest University School of Medicine) as well as the members of our laboratory for the many helpful comments. As to funding, silvestrol was provided through a National Cooperative Drug Discovery Group U19 [CA52956] and National Cancer Institute P01 [CA125066] to ADK. This work was supported by the National Cancer Institute [P01 CA081534 and P50 CA140158], The Samuel Waxman Cancer Research Foundation, and The Leukemia and Lymphoma Society.

Author information

Authors and Affiliations

  1. College of Pharmacy, The Ohio State University, Columbus, Ohio, USA

    Sneha V. Gupta, John C. Byrd, Li Pan, Kenneth K. Chan, A. Douglas Kinghorn, Mitch A. Phelps & David M. Lucas

  2. College of Medicine, The Ohio State University, Columbus, Ohio, USA

    Ellen J. Sass, Melanie E. Davis, Ryan B. Edwards, Gerard Lozanski, Nyla A. Heerema, John C. Byrd, Michael R. Grever & David M. Lucas

  3. Center for Biostatistics, The Ohio State University, Columbus, Ohio, USA

    Amy Lehman, Xiaoli Zhang & David Jarjoura

  4. The Ohio State University, 410 West 12th Ave., Room 455 OSUCCC Bldg., Columbus, Ohio, USA

    David M. Lucas

Authors
  1. Sneha V. Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ellen J. Sass
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Melanie E. Davis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ryan B. Edwards
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gerard Lozanski
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nyla A. Heerema
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Amy Lehman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiaoli Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. David Jarjoura
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. John C. Byrd
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Li Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kenneth K. Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. A. Douglas Kinghorn
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Mitch A. Phelps
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Michael R. Grever
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. David M. Lucas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David M. Lucas.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gupta, S.V., Sass, E.J., Davis, M.E. et al. Resistance to the Translation Initiation Inhibitor Silvestrol is Mediated by ABCB1/P-Glycoprotein Overexpression in Acute Lymphoblastic Leukemia Cells. AAPS J 13, 357–364 (2011). https://doi.org/10.1208/s12248-011-9276-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12248-011-9276-7

KEY WORDS

Search

Navigation