Advertisement

siRNA-Based Drug Targeting Human Bcl-xL Against Cancers

  • Yoshifumi TakeiEmail author
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1974)

Abstract

The 2006 discovery of the process of RNA interference opened the door to application of this phenomenon for disease treatments. Short interfering RNA (siRNA) can be used to induce RNA interference, and this approach has generated much interest as a new type of nucleic acid-based drugs in humans and other mammals. However, despite the great potential of siRNA-based drugs in cancer therapy, some drawbacks of siRNAs, such as their instability in vivo and poor cellular uptake, remain unresolved. Here, we review the development of siRNA-based drugs targeting the human Bcl-xL gene, an anti-apoptotic factor overexpressed in many cancers, including prostate cancers. We also introduce a novel application of the biomaterial atelocollagen as a vehicle to functionally deliver tumor-specific siRNA molecules in nude mice. Here, we introduce an orthotopic tumor inoculation model in nude mice: the resulting orthotopic tumors more closely replicate the clinical conditions in humans—including the metastasis mode—than ectopic subcutaneously inoculated tumors.

Keywords

Short interfering RNA (siRNA) Cancer therapy Bcl-xL Anti-apoptotic factor Prostate cancer Atelocollagen Anti-metastasis therapy 

References

  1. 1.
    Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T (2001) Duplexes of 21-nucleotide RNAs mediate interference in cultured mammalian cells. Nature 411:494–498CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391:806–811CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Carpenter AE, Sabatini DM (2004) Systematic genome-wide screens of gene function. Nat Rev Genet 5:11–22CrossRefPubMedGoogle Scholar
  4. 4.
    Zheng L, Liu J, Batalov S et al (2004) An approach to genomewide screens of expressed small interfering RNAs in mammalian cells. Proc Natl Acad Sci U S A 101:135–140CrossRefPubMedGoogle Scholar
  5. 5.
    Karagiannis TC, El-Osta A (2004) Mechanism of RNA interference, in vivo and potential clinical applications. Cancer Biol Ther 3:1069–1074CrossRefPubMedGoogle Scholar
  6. 6.
    Ryther RCC, Flynt AS, Phillips JA III, Patton JG (2005) siRNA therapeutics: big potential from small RNAs. Gene Ther 12:5–11CrossRefPubMedGoogle Scholar
  7. 7.
    Mu P, Nagahara S, Makita N, Tarumi Y, Kadomatsu K, Takei Y (2009) Systemic delivery of siRNA specific to tumor mediated by atelocollagen: combined therapy using siRNA targeting Bcl-xL and cisplatin against prostate cancer. Int J Cancer 125:2978–2990CrossRefPubMedGoogle Scholar
  8. 8.
    Boise LH, González-García M, Postema CE, Ding L, Lindsten T, Turka LA, Mao X, Nuñez G, Thompson CB (1993) bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 74:597–608CrossRefGoogle Scholar
  9. 9.
    Schott AF, Apel IJ, Nuñez G, Clarke MF (1995) Bcl-XL protects cancer cells from p53-mediated apoptosis. Oncogene 11:1389–1394PubMedGoogle Scholar
  10. 10.
    Yuan Y, Makita N, Cao D, Mihara K, Kadomatsu K, Takei Y (2015) Atelocollagen-mediated intravenous siRNA delivery specific to tumor tissues orthotopically xenografted in prostates of nude mice and its anticancer effects. Nucleic Acid Ther 25:85–94CrossRefPubMedGoogle Scholar
  11. 11.
    Ochiya T, Takahama Y, Nagahara S, Sumita Y, Hisada A, Itoh H, Nagai Y, Terada M (1999) New delivery system for plasmid DNA in vivo using atelocollagen as a carrier material: the Minipellet. Nat Med 5:707–710CrossRefPubMedGoogle Scholar
  12. 12.
    Takei Y, Kadomatsu K (2005) In vivo delivery technique of nucleic acid compounds using atelocollagen: its use in cancer therapeutics targeted at the heparin-binding growth factor midkine. Gene Ther Mol Biol 9:257–264Google Scholar
  13. 13.
    Fujimoto I, Takei Y (2014) Atelocollagen-mediated siRNA delivery: future promise for therapeutic application. Ther Deliv 5:369–371CrossRefPubMedGoogle Scholar
  14. 14.
    Inaba S, Nagahara S, Makita N, Tarumi Y, Ishimoto T, Matsuo S, Kadomatsu K, Takei Y (2012) Atelocollagen-mediated systemic delivery prevents immunostimulatory adverse effects of siRNA in mammals. Mol Ther 20:356–366CrossRefPubMedGoogle Scholar
  15. 15.
    Ishimoto T, Takei Y, Yuzawa Y, Hanai K, Nagahara S, Tarumi Y, Matsuo S, Kadomatsu K (2008) Downregulation of monocyte chemoattractant protein-1 involving short interfering RNA attenuates hapteninduced contact hypersensitivity. Mol Ther 16:387–395CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Medicinal Biochemistry, School of PharmacyAichi Gakuin UniversityNagoyaJapan

Personalised recommendations