CP-31398 prevents the growth of p53-mutated colorectal cancer cells in vitro and in vivo

Tumour Biol. 2015 Mar;36(3):1437-44. doi: 10.1007/s13277-014-2389-8. Epub 2015 Feb 8.

Abstract

Rescuing the function of mutant p53 protein is an attractive cancer therapeutic strategy. Small molecule CP-31398 was shown to restore mutant p53 tumor suppressor functions in cancer cells. Here, we determined the effects of CP-31398 on the growth of p53-mutated colorectal cancer (CRC) cells in vitro and in vivo. CRC cells which carry p53 mutation in codon 273 were treated with CP-31398 and the control, and the effects of CP-31398 on cell cycle, cell apoptosis, and proliferation were determined. The expression of p53-responsive downstream genes was evaluated by quantitative reverse transcriptase PCR (RT-PCR) and Western blot. CP-31398 was administrated into xenograft tumors created by the inoculation of HT-29 cells, and then the effect of CP-31398 on the growth of xenograft tumors was examined. CP-31398 induced p53 downstream target molecules in cultured HT-29 cells, which resulted in the inhibition of CRC cell growth assessed by the determination of cell cycle, apoptosis, and cell proliferation. In xenograft tumors, CP-31398 modulated the expression of Bax, Bcl-2, caspase 3, cyclin D, and Mdm2 and then blocked the growth of xenograft tumors. CP-31398 would be developed as a therapeutic candidate for p53-mutated CRC due to the restoration of mutant p53 tumor suppressor functions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Caspase 3 / genetics
  • Cell Cycle / drug effects
  • Cell Cycle / genetics
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology
  • Cyclin D / genetics
  • HT29 Cells
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Pyrimidines / pharmacology*
  • Tumor Suppressor Protein p53 / genetics*
  • Xenograft Model Antitumor Assays / methods
  • bcl-2-Associated X Protein / genetics

Substances

  • Cyclin D
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrimidines
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • bcl-2-Associated X Protein
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • Caspase 3
  • CP 31398