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Research Articles: Therapeutics, Targets, and Development

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

¹ Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, ² Department of Internal Medicine, ³ Advanced Medical Technology Cluster for Diagnosis and Prediction, and ⁴ KIST Regional Laboratory, The Advanced Medical Technology Cluster for Diagnosis and Prediction, School of Medicine, Kyungpook National University, Daegu, Korea and ⁵ College of Pharmacy, Seoul National University; and ⁶ Departments of Nuclear Medicine and Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine; ⁷ Biomedical Research Center, Korea Institute of Science and Technology, Seoul, Korea

Requests for reprints: In-San Kim, Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, 101 Dongin-2ga, Jung-gu, Daegu 700-422, Korea. Phone: 82-53-420-4821; Fax: 82-53-422-1466. E-mail: iskim{at}knu.ac.kr

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]

Grant support: Regional Technology Innovation Program of the MOCIE grant RT104-01-01, Advanced Medical Technology Cluster for Diagnosis and Prediction at Kyungpook National University, Ministry of Science and Technology Next Generation New Technology Development Program grant 10011353, and Brain Korea 21 Project in 2007.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: M-K. Kwon and J-O. Nam contributed equally to this work.

Received 8/29/07; revised 3/21/08; accepted 4/ 7/08.