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Correlating gene expression with chemical scaffolds of cytotoxic agents: ellipticines as substrates and inhibitors of MDR1

The Pharmacogenomics Journal volume 5, pages 112–125 (2005)Cite this article

Abstract

To facilitate a systematic study of chemoresistance across diverse classes of anticancer drug candidates, we performed correlation analyses between cytotoxic drug potency and gene expression in 60 tumor cell lines (NCI-60; NCI—National Cancer Institute). Ellipticine analogs displayed a range of correlation coefficients (r) with MDR1 (ABCB1, encoding multidrug resistance (MDR) protein MDR1 or P-glycoprotein). To determine MDR1 interactions of five ellipticines with diverse MDR1-r values, we employed MDR1-transport and cytotoxicity assays, using MDR1 inhibitors and siRNA-mediated MDR1 downregulation, in MDR1-overexpressing cells. Ellipticines with negative correlations—indicative of MDR1-mediated resistance—were shown to be MDR1 substrates, whereas those with neutral or positive correlations served as MDR1 inhibitors, which escape MDR1-mediated chemoresistance. Correlation with additional genes in the NCI-60 confirmed topoisomerases as ellipticine targets, but suggested distinct mechanisms of action and chemoresistance among them, providing a guide for selecting optimal drug candidates.

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Abbreviations

NCI:

the National Cancer Institute

5-FU:

5-fluorouracil

Pgp:

P-glycoprotein

MDR:

multidrug resistance

ABC:

ATP-binding cassette

siRNA:

small interfering RNA

RNAi:

RNA interference

SRB:

sulforhodamine B

CsA:

Cyclosporin A

R-123:

rhodamine-123

DNR:

daunorubicin

PCA:

principal component analysis

References

  1. Huang Y, Sadee W . Drug sensitivity and resistance genes in cancer chemotherapy: a chemogenomics approach. Drug Discov Today 2003; 8: 356–363.

    Article  CAS  Google Scholar 

  2. Scherf U, Ross DT, Waltham M, Smith LH, Lee JK, Tanabe L et al. A gene expression database for the molecular pharmacology of cancer. Nat Genet 2000; 24: 236–244.

    Article  CAS  Google Scholar 

  3. Huang Y, Anderle P, Bussey KJ, Barbacioru C, Shankavaram U, Dai Z et al. Membrane transporters and channels: role of the transportome in cancer chemosensitivity and chemoresistance. Cancer Res 2004; 64: 4294–4301.

    Article  CAS  Google Scholar 

  4. Chin KV, Pastan I, Gottesman MM . Function and regulation of the human multidrug resistance gene. Adv Cancer Res 1993; 60: 157–180.

    Article  CAS  Google Scholar 

  5. Gottesman MM, Pastan I . Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem 1993; 62: 385–427.

    Article  CAS  Google Scholar 

  6. 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: 627–638.

    CAS  PubMed  Google Scholar 

  7. 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: 2205–2214.

    Article  CAS  Google Scholar 

  8. Yusa K, Tsuruo T . Reversal mechanism of multidrug resistance by verapamil: direct binding of verapamil to P-glycoprotein on specific sites and transport of verapamil outward across the plasma membrane of K562/ADM cells. Cancer Res 1989; 49: 5002–5006.

    CAS  PubMed  Google Scholar 

  9. Sonneveld P, Durie BG, Lokhorst HM, Marie JP, Solbu G, Suciu S et al. Modulation of multidrug-resistant multiple myeloma by cyclosporin. The Leukaemia Group of the EORTC and the HOVON. Lancet 1992; 340: 255–259.

    Article  CAS  Google Scholar 

  10. Shi LM, Myers TG, Fan Y, O'Connor PM, Paull KD, Friend SH et al. Mining the National Cancer Institute Anticancer Drug Discovery Database: cluster analysis of ellipticine analogs with p53-inverse and central nervous system-selective patterns of activity. Mol Pharmacol 1998; 53: 241–251.

    Article  CAS  Google Scholar 

  11. Blower PE, Cross KP, Fligner MF, Myatt G, Verducci JS, Yang C et al. Systematic analysis of large screening sets. Curr Drug Disc Technol 2004; 1: 37–47.

    Article  CAS  Google Scholar 

  12. Everitt BS . Cluster Analysis. Halsted Press: New York, 1993.

    Google Scholar 

  13. Szakacs G, Annereau JP, Lababidi S, Shankavaram U, Arciello A, Bussey KJ et al. Predicting drug sensitivity and resistance: profiling ABC transporter genes in cancer cells. Cancer Cell 2004; 6: 129–137.

    Article  CAS  Google Scholar 

  14. Weinstein JN, Myers TG, O'Connor PM, Friend SH, Fornace Jr AJ, Kohn KW et al. An information-intensive approach to the molecular pharmacology of cancer. Science 1997; 275: 343–349.

    Article  CAS  Google Scholar 

  15. Kohn KW, Waring MJ, Glaubiger D, Friedman CA . Intercalative binding of ellipticine to DNA. Cancer Res 1975; 35: 71–76.

    CAS  PubMed  Google Scholar 

  16. Gribble GW . Synthesis and antitumor activity of ellipticine alkaloids and related compounds. In: Brossi A (ed). The Alkaloids: Chemistry and Pharmacology. Academic Press: San Diego, CA, 1990, pp 239–352.

    Google Scholar 

  17. Garbett NC, Graves DE . Extending nature's leads: the anticancer agent ellipticine. Curr Med Chem Anti-Cancer Agents 2004; 4: 149–172.

    Article  CAS  Google Scholar 

  18. Marie JP, Faussat-Suberville AM, Zhou D, Zittoun R . Daunorubicin uptake by leukemic cells: correlations with treatment outcome and mdr1 expression. Leukemia 1993; 7: 825–831.

    CAS  PubMed  Google Scholar 

  19. Roepe PD . What is the precise role of human MDR 1 protein in chemotherapeutic drug resistance? Curr Pharm Des 2000; 6: 241–260.

    Article  CAS  Google Scholar 

  20. Li D, Au JL . Mdr1 transfection causes enhanced apoptosis by paclitaxel: an effect independent of drug efflux function of P-glycoprotein. Pharmaceut Res 2001; 18: 907–913.

    Article  CAS  Google Scholar 

  21. Scala S, Akhmed N, Rao US, Paull K, Lan LB, Dickstein B et al. P-glycoprotein substrates and antagonists cluster into two distinct groups. Mol Pharmacol 1997; 51: 1024–1033.

    Article  CAS  Google Scholar 

  22. Wang EJ, Casciano CN, Clement RP, Johnson WW . In vitro flow cytometry method to quantitatively assess inhibitors of P-glycoprotein. Drug Metab Dispos 2000; 28: 522–528.

    CAS  PubMed  Google Scholar 

  23. Shapiro AB, Ling V . Positively cooperative sites for drug transport by P-glycoprotein with distinct drug specificities. Eur J Biochem 1997; 250: 130–137.

    Article  CAS  Google Scholar 

  24. Wang E, Casciano CN, Clement RP, Johnson WW . The farnesyl protein transferase inhibitor SCH66336 is a potent inhibitor of MDR1 product P-glycoprotein. Cancer Res 2001; 61: 7525–7529.

    CAS  PubMed  Google Scholar 

  25. Roberts G, Myatt GJ, Johnson WP, Cross KP, Blower Jr PE . LeadScope: software for exploring large sets of screening data. J Chem Inf Comput Sci 2000; 40: 1302–1314.

    Article  CAS  Google Scholar 

  26. Blower PE, Yang C, Fligner MA, Verducci JS, Yu L, Richman S et al. Pharmacogenomic analysis: correlating molecular substructure classes with microarray gene expression data. Pharmacogenomics J 2002; 2: 259–271.

    Article  CAS  Google Scholar 

  27. Wu L, Smythe AM, Stinson SF, Mullendore LA, Monks A, Scudiero DA et al. Multidrug-resistant phenotype of disease-oriented panels of human tumor cell lines used for anticancer drug screening. Cancer Res 1992; 52: 3029–3034.

    CAS  PubMed  Google Scholar 

  28. Monks A, Scudiero DA, Johnson GS, Paull KD, Sausville EA . The NCI anti-cancer drug screen: a smart screen to identify effectors of novel targets. Anticancer Drug Des 1997; 12: 533–541.

    CAS  PubMed  Google Scholar 

  29. Johnson RAW . D. W. Applied Multivariate Statistical Analysis. Prentice-Hall, Inc.: Upper Saddle River, NJ, 1998, pp 458–513.

    Google Scholar 

  30. Monks A, Scudiero D, Skehan P, Shoemaker R, Paull K, Vistica D et al. Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. J Natl Cancer Inst 1991; 83: 757–766.

    Article  CAS  Google Scholar 

  31. Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D et al. New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst 1990; 82: 1107–1112.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by NIH grant GM61390 and by funds from the Ohio State University.

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Author notes

  1. Y Huang

    Present address: Dana Farber Cancer Institute, Room D820D, 44 Binney St., Boston, MA, 02115, USA

Authors and Affiliations

  1. Department of Pharmacology, Comprehensive Cancer Center, College of Medicine and Public Health, The Ohio State University, Columbus, OH, USA

    Y Huang, Z Dai & W Sadée

  2. Leadscope Inc., Columbus, OH, USA

    P E Blower & C Yang

  3. Department of Biomedical Informatics, College of Medicine and Public Health, The Ohio State University, Columbus, OH, USA

    C Barbacioru

  4. College of Pharmacy, The Ohio State University, Columbus, OH, USA

    Y Zhang, J J Xiao & K K Chan

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Correspondence to P E Blower or W Sadée.

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Supplementary Information accompanies the paper on The Pharmacogenomics Journal website (http://www.nature.com/tpj).

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Huang, Y., Blower, P., Yang, C. et al. Correlating gene expression with chemical scaffolds of cytotoxic agents: ellipticines as substrates and inhibitors of MDR1. Pharmacogenomics J 5, 112–125 (2005). https://doi.org/10.1038/sj.tpj.6500297

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  • DOI: https://doi.org/10.1038/sj.tpj.6500297

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