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Anti-tumor activity of splice-switching oligonucleotides.

Abstract
Alternative splicing has emerged as an important target for molecular therapies. Splice-switching oligonucleotides (SSOs) modulate alternative splicing by hybridizing to pre-mRNA sequences involved in splicing and blocking access to the transcript by splicing factors. Recently, the efficacy of SSOs has been established in various animal disease models; however, the application of SSOs against cancer targets has been hindered by poor in vivo delivery of antisense therapeutics to tumor cells. The apoptotic regulator Bcl-x is alternatively spliced to express anti-apoptotic Bcl-x(L) and pro-apoptotic Bcl-x(S). Bcl-x(L) is upregulated in many cancers and is associated with chemoresistance, distinguishing it as an important target for cancer therapy. We previously showed that redirection of Bcl-x pre-mRNA splicing from Bcl-x(L) to -x(S) induced apoptosis in breast and prostate cancer cells. In this study, the effect of SSO-induced Bcl-x splice-switching on metastatic melanoma was assessed in cell culture and B16F10 tumor xenografts. SSOs were delivered in vivo using lipid nanoparticles. Administration of nanoparticle with Bcl-x SSO resulted in modification of Bcl-x pre-mRNA splicing in lung metastases and reduced tumor load, while nanoparticle alone or formulated with a control SSO had no effect. Our findings demonstrate in vivo anti-tumor activity of SSOs that modulate Bcl-x pre-mRNA splicing.
AuthorsJohn A Bauman, Shyh-Dar Li, Angela Yang, Leaf Huang, Ryszard Kole
JournalNucleic acids research (Nucleic Acids Res) Vol. 38 Issue 22 Pg. 8348-56 (Dec 2010) ISSN: 1362-4962 [Electronic] England
PMID20719743 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Bcl2l1 protein, mouse
  • Oligonucleotides
  • RNA Precursors
  • RNA, Messenger
  • bcl-X Protein
Topics
  • Alternative Splicing
  • Animals
  • Cell Line, Tumor
  • Female
  • Melanoma, Experimental (genetics, pathology, therapy)
  • Mice
  • Mice, Inbred C57BL
  • Nanoparticles (toxicity)
  • Oligonucleotides (administration & dosage, chemistry)
  • RNA Precursors (metabolism)
  • RNA, Messenger (metabolism)
  • bcl-X Protein (genetics, metabolism)

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