Targeting acute myeloid leukemia with a proapoptotic peptide conjugated to a Toll-like receptor 2-mediated cell-penetrating peptide.

Abstract

Cell-penetrating peptides provide a unique platform to create a new generation of cancer therapeutics with enhanced efficacy and diminished toxicity. In our study, enhanced expression of toll-like receptor 2 (TLR2) was observed in acute myeloid leukemia (AML) cells. Screening of a phage display peptide library using Biopanning and Rapid Analysis of Selective Interactive Ligands (BRASIL) identified a TLR2-binding peptide motif, Pep2. We show that the TLR2-binding peptide motif targeted and penetrated into leukemia cells in a TLR2-dependent manner. Moreover, a synthetic, chimeric peptide composed of the TLR2-binding motif linked to a programmed cell death-inducing sequence, D(KLAKLAK)2, induced apoptosis in AML cells with high TLR2 expression (TLR2(high)) but not in chronic myeloid leukemia (CML) cells with low TLR2 expression (TLR2(low)). The antileukemia activity of this chimeric peptide was confirmed in leukemia patient samples and an animal model of myeloid leukemia, as the development of leukemia was significantly delayed in mice with TLR2(high) AML compared to TLR2(low) CML NOD/SCID mice. TUNEL assays on bone marrow tissue slices revealed that the chimerical peptide induced leukemia cell apoptosis in a TLR2-dependent manner. Together, our findings indicate that TLR2 is a potential therapeutic target for the prevention and treatment of AML, and the prototype, Pep2-D(KLAKLAK)2, is a promising drug candidate in this setting.

• Authors: Ke Li, Xiao-Xi Lv, Fang Hua, Heng Lin, Wei Sun, Wen-Bin Cao, Xiao-Ming Fu, Jing Xie, Jiao-Jiao Yu, Zhe Li, Hong Liu, Ming-Zhe Han, Zhuo-Wei Hu
• Journal: International journal of cancer (Int J Cancer) Vol. 134 Issue 3 Pg. 692-702 (Feb 01 2014) ISSN: 1097-0215 [Electronic] United States
• PMID: 23852533 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 UICC.

Chemical References

• Peptides
• TLR2 protein, human
• Toll-Like Receptor 2

Topics

• Apoptosis
• Cell Line, Tumor
• Flow Cytometry
• Humans
• Leukemia, Myeloid, Acute (drug therapy, pathology)
• Peptides (chemistry, metabolism, pharmacokinetics, therapeutic use)
• Surface Plasmon Resonance
• Toll-Like Receptor 2 (chemistry, metabolism)