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Systemic co-administration of depsipeptide selectively targets transfection enhancement to specific tissues and cell types

Gene Therapy volume 13, pages 1724–1730 (2006)Cite this article

Abstract

Depsipeptide, a histone deacetylase (HDAC) inhibitor, kills tumor cells much more effectively than normal cells, and can produce significant antitumor activity in human cancer patients. Depsipeptide also increases the expression of lipoplex-delivered genes in cultured tumor cells, as well as following direct intra-tumoral injection. We now show that co-intravenous (i.v.) injection of depsipeptide with polyethylenimine (PEI):DNA complexes significantly increases the expression of PEI-delivered genes in normal, as well as in tumor-bearing mice. At the tissue level, depsipeptide-mediated enhancement of gene expression was selectively targeted to the lung, liver and spleen. At the cellular level, depsipeptide significantly increased the expression of the i.v., PEI co-delivered wild-type human p53 gene in metastatic breast cancer cells, but not in adjacent normal cells. Thus, the ability of depsipeptide to enhance the expression of systemically delivered genes is selectively targeted at both the tissue and cellular levels, without requiring the use of ligand- or promoter-based approaches. Analyzing HDAC-based targeting of gene expression may identify host genes that control the expression of systemically delivered genes.

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References

  1. Ueda H, Nakajima H, Hori Y, Goto T, Okuhara M . Action of FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum no. 968, on Ha-ras transformed NIH3T3 cells. Biosci Biotechnol Biochem 1994; 58: 1579–1583.

    Article  CAS  Google Scholar 

  2. Furumai R, Matsuyama A, Kobashi N, Lee KH, Nishiyama M, Nakajima H et al. FK228 (depsipeptide) as a natural prodrug that inhibits class I histone deacetylases. Cancer Res 2002; 62: 4916–4921.

    CAS  PubMed  Google Scholar 

  3. Byrd JC, Shinn C, Ravi R, Willis CR, Waselenko JK, Flinn IW et al. Depsipeptide (FR901228): a novel therapeutic agent with selective, in vitro activity against human B-cell chronic lymphocytic leukemia cells. Blood 1999; 94: 1401–1408.

    CAS  Google Scholar 

  4. Nakajima H, Kim YB, Terano H, Yoshida M, Horinouchi S . FR901228, a potent antitumor antibiotic, is a novel histone deacetylase inhibitor. Exp Cell Res 1998; 241: 126–133.

    Article  CAS  Google Scholar 

  5. Yoshida M, Horinouchi S, Beppu T . Trichostatin A and trapoxin: novel chemical probes for the role of histone acetylation in chromatin structure and function. Bioessays 1995; 17: 423–430.

    Article  CAS  Google Scholar 

  6. Wolffe AP, Pruss D . Targeting chromatin disruption: transcription regulators that acetylate histones. Cell 1996; 84: 817–819.

    Article  CAS  Google Scholar 

  7. Grunstein M . Histone acetylation in chromatin structure and transcription. Nature 1997; 389: 349–352.

    Article  CAS  Google Scholar 

  8. Condreay JP, Witherspoon SM, Clay WC, Kost TA . Transient and stable gene expression in mammalian cells transduced with a recombinant baculovirus vector. Proc Natl Acad Sci USA 1999; 96: 127–132.

    Article  CAS  Google Scholar 

  9. Yamano T, Ura K, Morishita R, Nakajima H, Monden M, Kaneda Y . Amplification of transgene expression in vitro and in vivo using a novel inhibitor of histone deacetylase. Mol Ther 2000; 1: 574–580.

    Article  CAS  Google Scholar 

  10. Goldsmith ME, Kitazono M, Fok P, Aikou T, Bates S, Fojo T . The histone deacetylase inhibitor FK228 preferentially enhances adenovirus transgene expression in malignant cells. Clin Cancer Res 2003; 9: 5394–5401.

    CAS  PubMed  Google Scholar 

  11. Handumrongkul C, Zhong W, Debs RJ . Distinct sets of cellular genes control the expression of transfected, nuclear-localized genes. Mol Ther 2002; 5: 186–194.

    Article  CAS  Google Scholar 

  12. Goula D, Benoist C, Mantero S, Merlo G, Levi G, Demeneix BA . Polyethylenimine-based intravenous delivery of transgenes to mouse lung. Gene Therapy 1998; 5: 1291–1295.

    Article  CAS  Google Scholar 

  13. Zou SM, Erbacher P, Remy JS, Behr JP . Systemic linear polyethylenimine (L-PEI)-mediated gene delivery in the mouse. J Gene Med 2000; 2: 128–134.

    Article  CAS  Google Scholar 

  14. Sasakawa Y, Naoe Y, Sogo N, Inoue T, Sasakawa T, Matsuo M et al. Marker genes to predict sensitivity to FK228, a histone deacetylase inhibitor. Biochem Pharmacol 2005; 69: 603–616.

    Article  CAS  Google Scholar 

  15. Sasakawa Y, Naoe Y, Noto T, Inoue T, Sasakawa T, Matsuo M et al. Antitumor efficacy of FK228, a novel histone deacetylase inhibitor, depends on the effect on expression of angiogenesis factors. Biochem Pharmacol 2003; 66: 897–906.

    Article  CAS  Google Scholar 

  16. Liu Y, Mounkes LC, Liggitt HD, Brown CS, Solodin I, Heath TD et al. Factors influencing the efficiency of cationic liposome-mediated intravenous gene delivery. Nat Biotechnol 1997; 15: 167–173.

    Article  CAS  Google Scholar 

  17. Coll JL, Chollet P, Brambilla E, Desplanques D, Behr JP, Favrot M . In vivo delivery to tumors of DNA complexed with linear polyethylenimine. Hum Gene Ther 1999; 10: 1659–1666.

    Article  CAS  Google Scholar 

  18. Felgner PL, Gadek TR, Holm M, Roman R, Chan HW, Wenz M et al. Lipofection: a highly efficient, lipid-mediated DNA-transfection procedure. Proc Natl Acad Sci USA 1987; 84: 7413–7417.

    Article  CAS  Google Scholar 

  19. Liu Y, Liggitt D, Zhong W, Tu G, Gaensler K, Debs R . Cationic liposome-mediated intravenous gene delivery. J Biol Chem 1995; 270: 24864–24870.

    Article  CAS  Google Scholar 

  20. Liu Y, Liggitt HD, Dow S, Handumrongkul C, Heath TD, Debs RJ . Strain-based genetic differences regulate the efficiency of systemic gene delivery as well as expression. J Biol Chem 2002; 277: 4966–4972.

    Article  CAS  Google Scholar 

  21. Liu Y, Thor A, Shtivelman E, Cao Y, Tu G, Heath TD et al. Systemic gene delivery expands the repertoire of effective antiangiogenic agents. J Biol Chem 1999; 274: 13338–13344.

    Article  CAS  Google Scholar 

  22. Wang H, Mohammad RM, Werdell J, Shekhar PV . p53 and protein kinase C independent induction of growth arrest and apoptosis by bryostatin 1 in a highly metastatic mammary epithelial cell line: In vitro versus in vivo activity. Int J Mol Med 1998; 1: 915–923.

    CAS  PubMed  Google Scholar 

  23. Chavez-Blanco A, Segura-Pacheco B, Perez-Cardenas E, Taja-Chayeb L, Cetina L, Candelaria M et al. Histone acetylation and histone deacetylase activity of magnesium valproate in tumor and peripheral blood of patients with cervical cancer. A phase I study. Mol Cancer 2005; 4: 22.

    Article  Google Scholar 

  24. Yamamoto S, Yamano T, Tanaka M, Hoon DS, Takao S, Morishita R et al. A novel combination of suicide gene therapy and histone deacetylase inhibitor for treatment of malignant melanoma. Cancer Gene Ther 2003; 10: 179–186.

    Article  CAS  Google Scholar 

  25. Byrd JC, Marcucci G, Parthun MR, Xiao JJ, Klisovic RB, Moran M et al. A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia. Blood 2005; 105: 959–967.

    Article  CAS  Google Scholar 

  26. Sandor V, Bakke S, Robey RW, Kang MH, Blagosklonny MV, Bender J et al. Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neoplasms. Clin Cancer Res 2002; 8: 718–728.

    CAS  Google Scholar 

  27. Liu F, Qi H, Huang L, Liu D . Factors controlling the efficiency of cationic lipid-mediated transfection in vivo via intravenous administration. Gene Therapy 1997; 4: 517–523.

    Article  CAS  Google Scholar 

  28. Schena M, Shalon D, Heller R, Chai A, Brown PO, Davis RW . Parallel human genome analysis: microarray-based expression monitoring of 1000 genes. Proc Natl Acad Sci USA 1996; 93: 10614–10619.

    Article  CAS  Google Scholar 

  29. Van Lint C, Emiliani S, Verdin E . The expression of a small fraction of cellular genes is changed in response to histone hyperacetylation. Gene Expr 1996; 5: 245–253.

    CAS  PubMed  Google Scholar 

  30. Peart MJ, Smyth GK, van Laar RK, Bowtell DD, Richon VM, Marks PA et al. Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors. Proc Natl Acad Sci USA 2005; 102: 3697–3702.

    Article  CAS  Google Scholar 

  31. Zhang J, Attar E, Cohen K, Crumpacker C, Scadden D . Silencing p21(Waf1/Cip1/Sdi1) expression increases gene transduction efficiency in primitive human hematopoietic cells. Gene Therapy 2005; 12: 1444–1452.

    Article  CAS  Google Scholar 

  32. Brunner S, Sauer T, Carotta S, Cotten M, Saltik M, Wagner E . Cell cycle dependence of gene transfer by lipoplex, polyplex and recombinant adenovirus. Gene Therapy 2000; 7: 401–407.

    Article  CAS  Google Scholar 

  33. Prasmickaite L, Hogset A, Berg K . The role of the cell cycle on the efficiency of photochemical gene transfection. Biochim Biophys Acta 2002; 1570: 210–218.

    Article  CAS  Google Scholar 

  34. Templeton NS, Lasic DD, Frederik PM, Strey HH, Roberts DD, Pavlakis GN . Improved DNA:liposome complexes for increased systemic delivery and gene expression. Nat Biotechnol 1997; 15: 647–652.

    Article  CAS  Google Scholar 

  35. Kircheis R, Blessing T, Brunner S, Wightman L, Wagner E . Tumor targeting with surface-shielded ligand–polycation DNA complexes. J Control Rel 2001; 72: 165–170.

    Article  CAS  Google Scholar 

  36. Shi N, Zhang Y, Zhu C, Boado RJ, Pardridge WM . Brain-specific expression of an exogenous gene after i.v. administration. Proc Natl Acad Sci USA 2001; 98: 12754–12759.

    Article  CAS  Google Scholar 

  37. Fong S, Liu Y, Heath T, Fong P, Liggitt D, Debs RJ . Membrane-permeant, DNA-binding agents alter intracellular trafficking and increase the transfection efficiency of complexed plasmid DNA. Mol Ther 2004; 10: 706–718.

    Article  CAS  Google Scholar 

  38. Fong S, Itahana Y, Sumida T, Singh J, Coppe JP, Liu Y et al. Id-1 as a molecular target in therapy for breast cancer cell invasion and metastasis. Proc Natl Acad Sci USA 2003; 100: 13543–13548.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by Grants CA96666 and CA109174 from the NIH-NCI to RJD.

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Authors and Affiliations

  1. California Pacific Medical Center Research Institute (CPMCRI), San Francisco, CA, USA

    Y Liu, S Fong & R J Debs

  2. Department of Comparative Medicine, University of Washington, Seattle, WA, USA

    D Liggitt

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Correspondence to R J Debs.

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Liu, Y., Liggitt, D., Fong, S. et al. Systemic co-administration of depsipeptide selectively targets transfection enhancement to specific tissues and cell types. Gene Ther 13, 1724–1730 (2006). https://doi.org/10.1038/sj.gt.3302825

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