title: Inhibitory effect of novel somatostatin peptide analogues on human cancer cell growth based on the selective inhibition of DNA polymerase β.
abstract: The present study was designed to investigate the anticancer activity of novel nine small peptides (compounds 1-9) derived from TT-232, a somatostatin structural analogue, by analyzing the inhibition of mammalian DNA polymerase (pol) and human cancer cell growth. Among the compounds tested, compounds 3 [tert-butyloxycarbonyl (Boc)-Tyr-Phe-1-naphthylamide], 4 (Boc-Tyr-Ile-1-naphthylamide), 5 (Boc-Tyr-Leu-1-naphthylamide) and 6 (Boc-Tyr-Val-1-naphthylamide) containing tyrosine (Tyr) but no carboxyl groups, selectively inhibited the activity of rat pol β, which is a DNA repair-related pol. Compounds 3-6 strongly inhibited the growth of human colon carcinoma HCT116 p53(+/+) cells. The influence of compounds 1-9 on HCT116 p53(-/-) cell growth was similar to that observed for HCT116 p53(+/+) cells. These results suggest that the cancer cell growth suppression induced by these compounds might be related to their inhibition of pol. Compound 4 was the strongest inhibitor of pol β and cancer cell growth among the nine compounds tested. This compound specifically inhibited rat pol β activity, but had no effect on the other 10 mammalian pols investigated. Compound 4 combined with methyl methane sulfonate (MMS) treatment synergistically suppressed HCT116 p53(-/-) cell growth compared with MMS alone. This compound also induced apoptosis in HCT116 cells with or without p53. From these results, the influence of compound 4, a specific pol β inhibitor, on the relationship between DNA repair and cancer cell growth is discussed.
authors.affiliation: Laboratory of Food & Nutritional Sciences, Faculty of Nutrition, Kobe Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180, Japan.
authors.forename: Isoko
authors.initials: I
authors.lastname: Kuriyama
authors.forename: Anna
authors.initials: A
authors.lastname: Miyazaki
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tsuda
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yoshida
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Mizushina
mesh_terms: D000818:Animals; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D045325:HCT116 Cells; D006801:Humans; D008741:Methyl Methanesulfonate / Q000633:toxicity; D019384:Nucleic Acid Synthesis Inhibitors; D051381:Rats; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000633:toxicity; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D004151:Dipeptides; D019384:Nucleic Acid Synthesis Inhibitors; D016159:Tumor Suppressor Protein p53; C581373:tert-butyloxycarbonyl-tyrosyl-isoleucyl-1-naphthylamide; D013004:Somatostatin; D008741:Methyl Methanesulfonate; D019951:DNA Polymerase beta; D004259:DNA-Directed DNA Polymerase