Antitumor effect of a transducible fusogenic peptide releasing multiple proapoptotic peptides by caspase-3

Mol Cancer Ther. 2008 Jun;7(6):1514-22. doi: 10.1158/1535-7163.MCT-07-2009.

Abstract

We have designed a novel peptide, TK3, composed of three functional domains, a protein transduction domain, a TAT followed by three tandem repeats of a proapoptotic peptide, and a caspase-3 cleavage site, (KLAKLAK)(2)-DEVD. TK3 was able to transduce into cells and then activate caspase-3, which in turn cleaved TK3 to release additional (KLAKLAK)(2) peptides. (KLAKLAK)(2) was well transduced by TAT into tumor cells and was able to induce apoptosis in vitro and in vivo. TK3 also induced apoptosis and inhibited angiogenesis in endothelial cells. Further, direct injection of TK3 into established B16F10 melanoma tumors in C57BL/6 mice resulted in almost complete inhibition of the tumor growth. These results suggest that TK3 could be beneficial for the treatment of accessible tumors and used as an adjuvant for cancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • CHO Cells
  • Caspase 3 / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cricetinae
  • Cricetulus
  • Endothelial Cells / drug effects
  • Endothelial Cells / pathology
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Neovascularization, Pathologic / pathology
  • Peptides / chemistry
  • Peptides / pharmacology*
  • Recombinant Fusion Proteins / metabolism*
  • Thymidine Kinase / metabolism
  • Transduction, Genetic*

Substances

  • Antineoplastic Agents
  • Peptides
  • Recombinant Fusion Proteins
  • Green Fluorescent Proteins
  • Thymidine Kinase
  • Caspase 3