Effect of an hdm-2 antagonist peptide inhibitor on cell cycle progression in p53-deficient H1299 human lung carcinoma cells

Oncogene. 2006 Oct 26;25(50):6672-7. doi: 10.1038/sj.onc.1209667. Epub 2006 May 29.


The hdm-2 oncogene is overexpressed in several types of malignancies including osteosarcomas, soft tissue sarcomas and gliomas and hdm-2 has been associated with accelerated tumor formation in both hereditary and sporadic cancers. Among the other key binding partners, hdm-2 forms a complex with the tumor suppressor p53, resulting in a rapid proteasome-mediated degradation of the p53 protein. This positions the hdm-2-p53 complex as an attractive target for the development of anticancer therapy and recently the first small molecule hdm-2 antagonist has been reported. Development of hdm-2 antagonists is currently focused on malignancies containing a wild-type p53 genotype, which is the case in approximately half of human cancer indications. However, hdm-2 has also been implicated in oncogenesis in the absence of p53. We therefore studied the effect of hdm-2 antagonists in p53-deficient human H1299 lung carcinoma cells. The hdm-2 antagonistic peptide caused G1 cell cycle arrest, inhibited colony growth and induced expression of G1 checkpoint regulatory proteins, such as p21(waf1,cip1). These data demonstrate that hdm-2 regulates the G1 cell cycle checkpoint in a p53-independent manner, suggesting that hdm-2 antagonists represent a novel class of anticancer therapeutics with broad applicability towards tumors with different p53 genetic backgrounds.

Publication types

  • Evaluation Study

MeSH terms

  • Carcinoma / genetics
  • Cell Cycle / drug effects*
  • Cell Proliferation / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Imidazoles / pharmacology
  • Lung Neoplasms / genetics*
  • Peptides / metabolism
  • Peptides / pharmacology*
  • Peptides / therapeutic use
  • Piperazines / pharmacology
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
  • Recombinant Fusion Proteins / metabolism
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / genetics*


  • Imidazoles
  • Peptides
  • Piperazines
  • Recombinant Fusion Proteins
  • Tumor Suppressor Protein p53
  • Green Fluorescent Proteins
  • nutlin 3
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2