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Updated: Sep 13, 2025

A Quantitative Measurement of Reactive Oxygen Species and Senescence-associated Secretory Phenotype in Normal Human Fibroblasts During Oncogene-induced Senescence
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Peptide Inhibitors Targeting FOXO4-p53 Interactions and Inducing Senescent Cancer Cell-specific Apoptosis

Donghoon Kang1, Yeji Lim1, Dabin Ahn1

  • 1Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.

Journal of Medicinal Chemistry
|July 31, 2025
PubMed

Insights

Researchers developed CPP-CAND, a peptide that targets therapy-induced senescent cancer cells. This peptide disrupts FOXO4-p53 interactions, inducing apoptosis and offering a new strategy against cancer recurrence.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Cellular senescence, characterized by cell cycle arrest and a secretory phenotype, is implicated in aging and cancer recurrence.
  • Chemotherapy-induced senescent cells can evade apoptosis, promoting tumor regrowth.
  • The nuclear interaction between FOXO4 and p53 is critical for senescent cell survival.

Purpose of the Study:

  • To investigate the structural basis of the FOXO4-p53 interaction.
  • To design and evaluate a novel peptide inhibitor targeting this interaction for cancer therapy.

Main Methods:

  • NMR spectroscopy was used to determine the binding interface between FOXO4 and p53.
  • A peptide inhibitor (CPP-CAND) was designed based on structural insights, incorporating a cationic cell-penetrating peptide (CPP) for improved delivery.
  • The efficacy and selectivity of CPP-CAND were assessed in senescent cancer cells.

Main Results:

  • Hydrophobic interactions within the p53 transactivation domain were identified as key for FOXO4 binding.
  • CPP-CAND demonstrated high selectivity for senescent cells, disrupting FOXO4-p53 complexes.
  • CPP-CAND induced caspase-dependent apoptosis in senescent cancer cells, including those treated with doxorubicin and cisplatin.

Conclusions:

  • The structural understanding of FOXO4-p53 interaction enabled the design of an effective peptide inhibitor.
  • CPP-CAND shows promise as a therapeutic agent for selectively eliminating therapy-induced senescent cancer cells.
  • This approach offers a potential strategy to overcome treatment resistance and prevent cancer recurrence.

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