Combining chemotherapeutic agents and netrin-1 interference potentiates cancer cell death

Andrea Paradisi, Marion Creveaux, Benjamin Gibert, Guillaume Devailly, Emeline Redoulez, David Neves, Elsa Cleyssac, Isabelle Treilleux, Christian Klein, Gerhard Niederfellner, Philippe A Cassier, Agnès Bernet, Patrick Mehlen

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

The secreted factor netrin-1 is upregulated in a fraction of human cancers as a mechanism to block apoptosis induced by netrin-1 dependence receptors DCC and UNC5H. Targeted therapies aiming to trigger tumour cell death via netrin-1/receptors interaction interference are under preclinical evaluation. We show here that Doxorubicin, 5-Fluorouracil, Paclitaxel and Cisplatin treatments trigger, in various human cancer cell lines, an increase of netrin-1 expression which is accompanied by netrin-1 receptors increase. This netrin-1 upregulation which appears to be p53-dependent is a survival mechanism as netrin-1 silencing by siRNA is associated with a potentiation of cancer cell death upon Doxorubicin treatment. We show that candidate drugs interfering with netrin-1/netrin-1 receptors interactions potentiate Doxorubicin, Cisplatin or 5-Fluorouracil-induced cancer cell death in vitro. Moreover, in a model of xenografted nude mice, we show that systemic Doxorubicin treatment triggers netrin-1 upregulation in the tumour but not in normal organs, enhancing and prolonging tumour growth inhibiting effect of a netrin-1 interfering drug. Together these data suggest that combining conventional chemotherapies with netrin-1 interference could be a promising therapeutic approach.

Original languageEnglish
Pages (from-to)1821-34
Number of pages14
JournalEMBO Molecular Medicine
Volume5
Issue number12
DOIs
Publication statusPublished - Dec 2013
Externally publishedYes

Keywords / Materials (for Non-textual outputs)

  • Animals
  • Antineoplastic Agents
  • Apoptosis
  • Cell Line, Tumor
  • Cisplatin
  • Doxorubicin
  • Female
  • Fluorouracil
  • Humans
  • Lung Neoplasms
  • Mice
  • Mice, Nude
  • Nerve Growth Factors
  • RNA Interference
  • RNA, Small Interfering
  • Receptors, Cell Surface
  • Transplantation, Heterologous
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Up-Regulation

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