title: 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.affiliation: Molecular Immunology and Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China.
authors.forename: Ke
authors.initials: K
authors.lastname: Li
authors.forename: Xiao-Xi
authors.initials: XX
authors.lastname: Lv
authors.forename: Fang
authors.initials: F
authors.lastname: Hua
authors.forename: Heng
authors.initials: H
authors.lastname: Lin
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Cao
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Fu
authors.forename: Jing
authors.initials: J
authors.lastname: Xie
authors.forename: Jiao-Jiao
authors.initials: JJ
authors.lastname: Yu
authors.forename: Zhe
authors.initials: Z
authors.lastname: Li
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Ming-Zhe
authors.initials: MZ
authors.lastname: Han
authors.forename: Zhuo-Wei
authors.initials: ZW
authors.lastname: Hu
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020349:Surface Plasmon Resonance; D051195:Toll-Like Receptor 2 / Q000737:chemistry* / Q000378:metabolism
chemical_list: D010455:Peptides; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2
keywords: apoptosis; cancer therapy; cell-penetrating peptide; targeted drug delivery