Distinct biological responses of metastatic castration resistant prostate cancer cells upon exposure to G-quadruplex interacting naphthalenediimide derivatives

Marta Recagni, Maria Laura Greco, Andrea Milelli, Anna Minarini, Nadia Zaffaroni, Marco Folini, Claudia Sissi

Research output: Contribution to journalArticlepeer-review

Abstract

Small molecules able to bind non-canonical G-quadruplex DNA structures (G4) have been recently tested as novel potential agents for the treatment of prostate cancer thanks to their repression of aberrant androgen receptor gene. However, metastatic castration-resistant prostate cancer (mCRPC), a letal form of prostate cancer, is still incurable. Here we tested two naphthalenediimide derivatives, previously reported as multitarget agents, on a couple of relevant mCRPC cell models (DU145 and PC-3). We showed that these compounds interfere with the RAS/MEK/ERK and PI3K/AKT pathways. Interestingly, both these two biological processes depend upon Epidermal Growth Factor Receptor (EGFR) activation. By means of biological and analytical tools we showed that our compounds are efficient inducers of the structural transition of the EGFR promoter towards a G-quadruplex conformation, ultimately leading to a reduction of the receptor production. The overall result is an interesting cytotoxic profile for these two derivatives. Thanks to their activity at different steps, these compounds can open the way to novel therapeutic approaches for mCRPC that could contribute to escape resistance to selective treatments.

Original languageEnglish
Pages (from-to)401-413
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume177
DOIs
Publication statusPublished - Sep 1 2019

Keywords

  • C-circle DNA
  • Epidermal growth factor receptor
  • G-quadruplex
  • Gene promoter
  • Naphthalenediimide
  • Prostate cancer

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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