title: Perhexiline maleate enhances antitumor efficacy of cisplatin in neuroblastoma by inducing over-expression of NDM29 ncRNA.
abstract: High Risk Neuroblastoma (HR-NB) is a pediatric cancer characterized by high malignancy and remarkable cell heterogeneity within the tumour nodules. In a recent study, we demonstrated that in vitro and in vivo over-expression of the non-coding RNA NDM29 (neuroblastoma differentiation marker 29) induces NB cell differentiation, dramatically reducing their malignancy. Among gene expression changes, differentiated phenotype induced by NDM29 is characterized by decrease of the expression of ABC transporters responsible for anticancer drug resistance. Thus, the pharmacological induction of NDM29, in principle, might represent a possible novel strategy to increase cytotoxic drug responses. In this work, we identify a small molecule able to induce the expression of NDM29 in NB cells, conferring to malignant cells increased susceptibility to cisplatin cytotoxic effects. We demonstrate that the pharmacological induction of NDM29 expression in vivo enhances the antitumoral effects of chemotherapy specifically on tumour initiating/cancer stem cells sub-population, usually refractory to therapies and responsible for tumour relapse. In summary, we suggest a novel therapeutical approach possibly useful to treat very aggressive NB cases with poor prognosis. This novel pharmacological strategy aims to promote differentiation of "stem-like" cells to render them more susceptible to the killing action of cytotoxic anticancer drugs.
authors.affiliation: Dept. of Experimental Medicine (DIMES), University of Genova, Genova, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Vella
authors.affiliation: Dept. of Experimental Medicine (DIMES), University of Genova, Genova, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Penna
authors.affiliation: IRCCS-AOU San Martino-IST, Genova, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Longo
authors.affiliation: Dept. of Experimental Medicine (DIMES), University of Genova, Genova, Italy.|IRCCS-AOU San Martino-IST, Genova, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Pioggia
authors.affiliation: Dept. of Experimental Medicine (DIMES), University of Genova, Genova, Italy.|IRCCS-AOU San Martino-IST, Genova, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Garbati
authors.affiliation: Sect. of Pharmacology, Dept. of Internal Medicine (DiMI) and Center of Excellence for Biomedical Research (CEBR), University of Genova, Genova, Italy.
authors.forename: Tullio
authors.initials: T
authors.lastname: Florio
authors.affiliation: The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Fabio
authors.initials: F
authors.lastname: Rossi
authors.affiliation: Dept. of Experimental Medicine (DIMES), University of Genova, Genova, Italy.|IRCCS-AOU San Martino-IST, Genova, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Pagano
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D010480:Perhexiline / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D022661:RNA, Untranslated / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D018528:ATP-Binding Cassette Transporters; C576282:NDM29 non-coding RNA, human; D022661:RNA, Untranslated; C023470:perhexiline maleate; D010480:Perhexiline; D002945:Cisplatin