Cell‐penetrating cebpb and cebpd leucine zipper decoys as broadly acting anti‐cancer agents

Qing Zhou, Xiotian Sun, Nicolas Pasquier, Parvaneh Jefferson, Trang T.T. Nguyen, Markus D. Siegelin, James M. Angelastro, Lloyd A. Greene

Research output: Contribution to journalArticlepeer-review

Abstract

Transcription factors are key players underlying cancer formation, growth, survival, metastasis and treatment resistance, yet few drugs exist to directly target them. Here, we charac-terized the in vitro and in vivo anti‐cancer efficacy of novel synthetic cell‐penetrating peptides (Bpep and Dpep) designed to interfere with the formation of active leucine‐zipper‐based dimers by CEBPB and CEBPD, transcription factors implicated in multiple malignancies. Both peptides sim-ilarly promoted apoptosis of multiple tumor lines of varying origins, without such effects on non‐transformed cells. Combined with other treatments (radiation, Taxol, chloroquine, doxorubi-cin), the peptides acted additively to synergistically and were fully active on Taxol‐resistant cells. The peptides suppressed expression of known direct CEBPB/CEBPD targets IL6, IL8 and aspara-gine synthetase (ASNS), supporting their inhibition of transcriptional activation. Mechanisms by which the peptides trigger apoptosis included depletion of pro‐survival survivin and a required elevation of pro‐apoptotic BMF. Bpep and Dpep significantly slowed tumor growth in mouse models without evident side effects. Dpep significantly prolonged survival in xenograft models. These findings indicate the efficacy and potential of Bpep and Dpep as novel agents to treat a va-riety of cancers as mono‐ or combination therapies.

Original languageEnglish (US)
Article number2504
JournalCancers
Volume13
Issue number10
DOIs
StatePublished - May 2 2021

Keywords

  • ATF5
  • CEBPB
  • CEBPD
  • Decoy
  • Transcription factor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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