title: Enhanced targeted anticancer effects and inhibition of tumor metastasis by the TMTP1 compound peptide TMTP1-TAT-NBD.
abstract: Micromolecular agents that block tumor development and metastasis hold great promise as cancer-targeted therapies. Tumor molecular targeted peptide 1 (TMTP1) was previously shown to target primary tumors and metastatic foci specifically. In this study, a group of composite peptides were incorporated to TMPT1. The NF-κB essential modulator-binding domain (NBD), and the trans-activator of transcription (TAT) peptide, were synthesized to enhance the targeted anti-tumor effects of TMTP1. TMTP1-NBD did not exhibit strong affinity to tumor cells as we had expected. Conjugating TAT with TMTP1-NBD ameliorated the poor hydrophilicity and negative charge of TMTP1-NBD. Therefore TMTP1-TAT-NBD displayed strong affinity and anti-tumor effects as we expected in vivo and in vitro. Interestingly cytoplasmic glycogen accumulation as well as apoptosis was observed in TMTP1-TAT-NBD treated PC-3M-1E8 cells. The downstream signaling pathways including AKT, GSK-3β, IκBα and NF-κB activity were verified to decrease by TMTP1-TAT-NBD. The pharmacokinetics and distribution of TMTP1-TAT-NBD in MDA-MB-231 tumor-bearing mice model provided some evidence for safety of the composite peptide, which showed the fluorescence of the peptide peaked in the tumor 6h after injection, with little fluorescence detected in normal organs except for very weak fluorescence in kidney. In conclusion, TMTP1-TAT-NBD may be a promising targeted anti-tumor agent for primary tumor and metastatic foci, which enhances the anticancer effects through inhibiting the AKT/GSK-3β/NF-κB pathway comparing with TMTP1.
authors.affiliation: Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China.
authors.forename: Ronghua
authors.initials: R
authors.lastname: Liu
authors.forename: Ling
authors.initials: L
authors.lastname: Xi
authors.forename: Danfeng
authors.initials: D
authors.lastname: Luo
authors.forename: Xiangyi
authors.initials: X
authors.lastname: Ma
authors.forename: Wanhua
authors.initials: W
authors.lastname: Yang
authors.forename: Yandong
authors.initials: Y
authors.lastname: Xi
authors.forename: Hongyan
authors.initials: H
authors.lastname: Wang
authors.forename: Ming
authors.initials: M
authors.lastname: Qian
authors.forename: Liangsheng
authors.initials: L
authors.lastname: Fan
authors.forename: Xi
authors.initials: X
authors.lastname: Xia
authors.forename: Kezheng
authors.initials: K
authors.lastname: Li
authors.forename: Daowen
authors.initials: D
authors.lastname: Wang
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Zhou
authors.forename: Li
authors.initials: L
authors.lastname: Meng
authors.forename: Shixuan
authors.initials: S
authors.lastname: Wang
authors.forename: Ding
authors.initials: D
authors.lastname: Ma
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009842:Oligopeptides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D057846:Cell-Penetrating Peptides; C575063:IKK NBD peptide; D009842:Oligopeptides; D010446:Peptide Fragments; C531959:asparagyl-valyl-valyl-arginyl-glutamine; D054322:tat Gene Products, Human Immunodeficiency Virus; C497137:tat peptide (47-57), Human immunodeficiency virus 1