title: Systemic transduction of p16INK4A antitumor peptide inhibits the growth             of MBT-2 mouse bladder tumor cell line grafts.
abstract: p16(INK4a) (p16), a key molecule in bladder tumor development, inhibits the activities of cyclin-dependent kinases (CDKs) and maintains the retinoblastoma protein (pRb) in its active hypophosphorylated state. Following the finding that the p16 antitumor peptide dramatically inhibits the growth of aggressive leukemia/lymphoma through the restoration of p16 function using the Wr-T peptide transporter system, in this study, we developed a systemic therapy using mouse‑p16 peptide (m‑p16) in subcutaneous p16‑null mouse bladder tumors. In vitro analysis showed that the growth of p16‑null bladder tumor cells and the hyperphosphorylation of their pRbs were inhibited by p16 transduction in a concentration‑dependent manner. In an animal model, p16‑null MBT‑2 cells were injected subcutaneously into KSN/SKC nude mice. The systemic delivery of the m‑p16 peptide using Wr‑T by cardiac injection significantly inhibited the growth of solid MBT‑2 tumors compared with the control phosphate‑buffered saline (PBS) injection. Histological examination by TUNEL staining revealed that apoptosis was increased and pRb phosphorylation was inhibited. Thus, the systemic peptide delivery of p16 restores the hypophosphorylation of pRb and may be a useful tool for the treatment of bladder tumors.
authors.affiliation: Department of Urology, Ibaraki Clinical Education and Training Center, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. torushim@md.tsukuba.ac.jp
authors.forename: Toru
authors.initials: T
authors.lastname: Shimazui
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yoshikawa
authors.forename: Jun
authors.initials: J
authors.lastname: Miyazaki
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kojima
authors.forename: Hiromu
authors.initials: H
authors.lastname: Inai
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ando
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Uemura
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Uchida
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nishiyama
mesh_terms: D000818:Animals; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000008:administration & dosage* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D010455:Peptides / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism; D014184:Transplantation, Homologous; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D010455:Peptides; D016160:Retinoblastoma Protein