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

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 (p14ARF and p16INK4a or p16INK4a and p21CIP1 functional peptides) compared with single-peptide introduction using Wr-T-mediated peptide delivery. Wr-T-mediated transport of both p14ARF and p16 INK4a functional peptides (p14-1C and p16-MIS, respectively) into human glioblastoma cell line, U87ΔEGFR, 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 Gli36ΔEGFR, 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. Copyright © 2008 American Association for Cancer Research.