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Research Articles: Therapeutics, Targets, and Development

Potent synergy of dual antitumor peptides for growth suppression of human glioblastoma cell lines

Departments of ¹ Pathology and ² Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences; ³ Department of Human Nutrition, Chugokugakuen University, Okayama, Japan; ⁴ R&D Center, Katayama Chemical Industries Co., Ltd., Osaka, Japan; ⁵ Research Complex for the Medicine Frontiers, Aichi Medical University School of Medicine, Aichi, Japan; and ⁶ Department of Medical Oncology and Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

Requests for reprints: Eisaku Kondo, Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. Phone: 81-86-235-7152; Fax: 81-86-235-7156. E-mail: ekondo{at}md.okayama-u.ac.jp

Abstract

Molecular targeting agents have become formidable anticancer weapons, which show much promise against the refractory tumors. Functional peptides are among the more desirable of these nanobio-tools. Intracellular delivery of multiple functional peptides forms a basis for potent, non-invasive mode of delivery, providing distinctive therapeutic advantages. Here, we examine growth suppression efficiency of human glioblastomas by dual-peptide targeting. We did simultaneous introduction of two tumor suppressor peptides (p14^ARF and p16^INK4a or p16^INK4a and p21^CIP1 functional peptides) compared with single-peptide introduction using Wr-T-mediated peptide delivery. Wr-T-mediated transport of both p14^ARF and p16^INK4a functional peptides (p14-1C and p16-MIS, respectively) into human glioblastoma cell line, U87EGFR, reversed specific loss of p14 and p16 function, thereby drastically inhibiting tumor growth by >95% within the first 72 h, whereas the growth inhibition was 40% by p14 or p16 single-peptide introduction. Additionally, the combination of p16 and p21^CIP1 (p21-S154A) peptides dramatically suppressed the growth of glioblastoma line Gli36EGFR, which carries a missense mutation in p53, by >97% after 120 h. Significantly, our murine brain tumor model for dual-peptide delivery showed a substantial average survival enhancement (P < 0.0001) for peptide-treated mice. Wr-T-mediated dual molecular targeting using antitumor peptides is highly effective against growth of aggressive glioblastoma cells in comparison with single molecule targeting. Thus, jointly restoring multiple tumor suppressor functions by Wr-T-peptide delivery represents a powerful approach, with mechanistic implications for development of efficacious molecular targeting therapeutics against intractable human malignancies. [Mol Cancer Ther 2008;7(6):1461–71]

Grant support: Kiban (C) Grants-in-Aid for Scientific Research, Japanese Ministry of Education, Culture, Sports, Science and Technology grant 16590279.

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: E. Kondo and T. Tanaka contributed equally to this work.

⁷ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 8/29/07; revised 2/21/08; accepted 4/ 2/08.