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

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. [Mol Cancer Ther 2008;7(6):1514 -22]

Cellular uptake and in vivo distribution of polyhistidine peptides

“…This result indicates that the PAD-H16 peptide can transit cytosol and exhibit cytotoxicity. However, previous studies reported that the PAD conjugated to the TAT-peptide showed cytotoxicity at a lower concentration (IC 50 = 5~10 µM)[33] than the PAD-H16 peptide (IC 50 = 62 µM), although against different cell lines. This low cytotoxicity of the PAD-H16 peptide is thought to be due to level of macropinosome escape.…”

Systemic Delivery of Tumor-Targeted Bax-Derived Membrane-Active Peptides for the Treatment of Melanoma Tumors in a Humanized SCID Mouse Model

“…33,34 The tumor-targeted delivery of cytotoxic peptides (e.g., [KLAKLAK] 2 ) was initially of interest for the treatment of tumors, [35][36][37][38] particularly melanoma, when targeted by cRGD 39 or with a cell-penetrating peptide, such as TAT. 40 However, despite promising results, no follow-up studies have been reported on these compounds, certainly because of the modest activity of (KLAKLAK) 2 .…”

Evaluation of the use of therapeutic peptides for cancer treatment

“…In order to overcome their poor cell permeability; various CPPs have been used to enhance the intracellular delivery of peptides [67]. The Tat peptide was conjugated with multiple pro-apoptotic peptides (KLAKLAK) 2 separated by a caspase-3 cleavage site [68]. When this peptide was taken by mouse melanoma and human breast cancer cells, it activated endogenous caspase-3 which then cleaved the Tat-KLA peptide resulting in release of the pro-apoptotic peptide (KLAKLAK) 2 [68].…”