title: Synergistic tumor growth-inhibitory effect of the prostate-specific antigen-activated fusion peptide BSD352 for prostate cancer therapy.
abstract: Prostate-specific antigen (PSA), a serine protease, is a promising target for the development of prodrugs in prostate cancer treatment. In this study, we designed a novel fusion peptide, BSD352, containing three functional domains: a protein transduction domain from HIV transactivating regulatory protein (TAT) followed by the BH3 domain of the p53 upregulated modulator of apoptosis (TAT-BH3), an anti-vascular endothelial growth factor peptide (SP5.2), and an anti-basic fibroblast growth factor peptide (DG2). These different domains in BSD352 were linked together by a linker sequence corresponding to a PSA hydrolytic substrate peptide. The BSD352 fusion peptide could be selectively cleaved by PSA in PSA-producing LNCaP prostate cancer cells. Furthermore, the BSD352 fusion peptide was efficiently transduced into tumor cells both in vitro and in vivo, and the BH3 domain was found to induce tumor cell apoptosis by elevating the expression of Bax, cytochrome C release, and caspase-9 cleavage. Moreover, the SP5.2 and DG2 domains in the BSD352 fusion peptide also exhibited in-vitro endothelial cell growth inhibition and in-vivo antiangiogenic activities. Direct injection of BSD352 into an established LNCaP xenograft tumor in mice inhibited tumor growth, whereas a synergistic effect was observed with the combined use of wild-type BH3, SP5.2, and DG2 functional domains. These results suggest that BSD352 could be beneficial for the treatment of accessible prostate tumors and may provide a complementary strategy for prostate cancer therapy.
authors.affiliation: Department of Laboratory Medicine, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Zhang
authors.forename: Zhou-Liang
authors.initials: ZL
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Long
authors.forename: Ji-Hong
authors.initials: JH
authors.lastname: Ren
authors.forename: Fang
authors.initials: F
authors.lastname: Lin
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.forename: Jun-Xia
authors.initials: JX
authors.lastname: Wei
authors.forename: Ke
authors.initials: K
authors.lastname: Dong
authors.forename: Hui-Zhong
authors.initials: HZ
authors.lastname: Zhang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D017209:Apoptosis; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D011467:Prostate / Q000166:cytology / Q000187:drug effects; D017430:Prostate-Specific Antigen / Q000097:blood / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D011897:Random Allocation; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; C560499:BSD352 peptide; D011993:Recombinant Fusion Proteins; D017430:Prostate-Specific Antigen