title: Combining chemotherapeutic agents and netrin-1 interference potentiates cancer cell death.
abstract: 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.
authors.affiliation: Apoptosis, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, Lyon, France.
authors.forename: Andrea
authors.initials: A
authors.lastname: Paradisi
authors.forename: Marion
authors.initials: M
authors.lastname: Creveaux
authors.forename: Benjamin
authors.initials: B
authors.lastname: Gibert
authors.forename: Guillaume
authors.initials: G
authors.lastname: Devailly
authors.forename: Emeline
authors.initials: E
authors.lastname: Redoulez
authors.forename: David
authors.initials: D
authors.lastname: Neves
authors.forename: Elsa
authors.initials: E
authors.lastname: Cleyssac
authors.forename: Isabelle
authors.initials: I
authors.lastname: Treilleux
authors.forename: Christian
authors.initials: C
authors.lastname: Klein
authors.forename: Gerhard
authors.initials: G
authors.lastname: Niederfellner
authors.forename: Philippe A
authors.initials: PA
authors.lastname: Cassier
authors.forename: Agnès
authors.initials: A
authors.lastname: Bernet
authors.forename: Patrick
authors.initials: P
authors.lastname: Mehlen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000633:toxicity; D004317:Doxorubicin / Q000627:therapeutic use / Q000633:toxicity; D005260:Female; D005472:Fluorouracil / Q000633:toxicity; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000075386:Netrin Receptors; D000075388:Netrin-1; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; C000617353:Ntn1 protein, mouse; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C532445:UNC5B protein, human; D000075388:Netrin-1; D004317:Doxorubicin; D002945:Cisplatin; D005472:Fluorouracil
keywords: DCC; cancer therapy; dependence receptor; netrin-1, p53