Inhibitory Effect of Novel Somatostatin Peptide Analogues on Human Cancer Cell Growth Based on the Selective Inhibition of DNA Polymerase β

Bioorg Med Chem. 2013 Jan 15;21(2):403-11. doi: 10.1016/j.bmc.2012.11.024. Epub 2012 Nov 29.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cattle
  • Cell Proliferation / drug effects
  • DNA Fragmentation / drug effects
  • DNA Polymerase beta / antagonists & inhibitors*
  • DNA Polymerase beta / metabolism
  • DNA-Directed DNA Polymerase / metabolism
  • Dipeptides / chemical synthesis
  • Dipeptides / chemistry*
  • Dipeptides / toxicity
  • HCT116 Cells
  • Humans
  • Methyl Methanesulfonate / toxicity
  • Nucleic Acid Synthesis Inhibitors
  • Rats
  • Somatostatin / analogs & derivatives*
  • Somatostatin / toxicity
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Dipeptides
  • Nucleic Acid Synthesis Inhibitors
  • Tumor Suppressor Protein p53
  • tert-butyloxycarbonyl-tyrosyl-isoleucyl-1-naphthylamide
  • Somatostatin
  • Methyl Methanesulfonate
  • DNA Polymerase beta
  • DNA-Directed DNA Polymerase