title: DT390-triTMTP1, a novel fusion protein of diphtheria toxin with tandem repeat TMTP1 peptide, preferentially targets metastatic tumors.
abstract: Peptide-based therapies have emerged as one of the most promising therapeutics strategy in cancer-targeted therapy. Using our laboratory newly identified peptide TMTP1 and diphtheria toxin, we developed a new fusion protein that showed remarkable ability to target highly metastatic tumors. Fusion protein toxins were generated by fusing the first 390 amino acids of diphtheria toxin [truncated diphtheria toxin (DT390)] to different repeats of peptide TMTP1 (DT390-TMTP1, DT390-biTMTP1, and DT390-triTMTP1). Efficacies of the recombinant fusion proteins on tumor growth and metastasis were evaluated in vitro and in vivo. DT390-triTMTP1 showed the most powerful toxicity against cancer, which led to tumor growth retardation or regression and prolonged survival of human prostate cancer PC-3M-1E8 subcutaneously bearing or gastric cancer MKN-45 orthotopic nude mice. Increased TUNEL and caspase-3 staining and reduced ki67 staining in tumor cells suggested that the anticancer effects of DT390-triTMTP1 were through selectively inducing apoptosis and inhibiting proliferation of cancer cells. In a murine model of human orthotopic gastric carcinoma, DT390-biTMTP1 significantly inhibited metastases to liver and spleen, while DT390-triTMTP1 not only totally suppressed metastasis but also reduced primary tumors by 66.6%. In the biodistribution test, DT390-triTMTP1 was observed to home to tumor tissue rapidly and lasted over 48 h, with only a transient appearance in liver and kidney immediately after injection. Thus, our present study provided a novel recombinant fusion protein DT390-triTMTP1 with preferential targeting and high cytotoxicity, which may be a promising strategy for the targeted therapy of cancer metastasis.
authors.affiliation: Cancer Biology Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei 430030, People's Republic of China.
authors.forename: Xiangyi
authors.initials: X
authors.lastname: Ma
authors.forename: Peng
authors.initials: P
authors.lastname: Lv
authors.forename: Shuangmei
authors.initials: S
authors.lastname: Ye
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Shu
authors.initials: S
authors.lastname: Li
authors.forename: Chunyi
authors.initials: C
authors.lastname: Kan
authors.forename: Liangsheng
authors.initials: L
authors.lastname: Fan
authors.forename: Ronghua
authors.initials: R
authors.lastname: Liu
authors.forename: Danfeng
authors.initials: D
authors.lastname: Luo
authors.forename: Aiping
authors.initials: A
authors.lastname: Wang
authors.forename: Wanhua
authors.initials: W
authors.lastname: Yang
authors.forename: Shuhong
authors.initials: S
authors.lastname: Yang
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Bai
authors.forename: Yunping
authors.initials: Y
authors.lastname: Lu
authors.forename: Ding
authors.initials: D
authors.lastname: Ma
authors.forename: Ling
authors.initials: L
authors.lastname: Xi
authors.forename: Shixuan
authors.initials: S
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004167:Diphtheria Toxin / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009842:Oligopeptides / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000473:pathology; D020080:Tandem Repeat Sequences; D014018:Tissue Distribution
chemical_list: D004167:Diphtheria Toxin; D009842:Oligopeptides; D010455:Peptides; D011993:Recombinant Fusion Proteins; C531959:asparagyl-valyl-valyl-arginyl-glutamine