title: Valproic acid inhibits adhesion of vincristine- and cisplatin-resistant neuroblastoma tumour cells to endothelium.
abstract: Drug resistance to chemotherapy is often associated with increased malignancy in neuroblastoma (NB). In pursuit of alternative treatments for chemoresistant tumour cells, we tested the response of multidrug-resistant SKNSH and of vincristine (VCR)-, doxorubicin (DOX)-, or cisplatin (CDDP)-resistant UKF-NB-2, UKF-NB-3 or UKF-NB-6 NB tumour cell lines to valproic acid (VPA), a differentiation inducer currently in clinical trials. Drug resistance caused elevated NB adhesion (UKF-NB-2(VCR), UKF-NB-2(DOX), UKF-NB-2(CDDP), UKF-NB-3(VCR), UKF-NB-3(CDDP), UKF-NB-6(VCR), UKF-NB-6(CDDP)) to an endothelial cell monolayer, accompanied by downregulation of the adhesion receptor neural cell adhesion molecule (NCAM). Based on the UKF-NB-3 model, N-myc proteins were enhanced in UKF-NB-3(VCR) and UKF-NB-3(CDDP), compared to the drug naïve controls. p73 was diminished, whereas the p73 isoform deltaNp73 was upregulated in UKF-NB-3(VCR) and UKF-NB-3(CDDP). Valproic acid blocked adhesion of UKF-NB-3(VCR) and UKF-NB-3(CDDP), but not of UKF-NB-3(DOX), and induced the upregulation of NCAM surface expression, NCAM protein content and NCAM coding mRNA. Valproic acid diminished N-myc and enhanced p73 protein level, coupled with downregulation of deltaNp73 in UKF-NB-3(VCR) and UKF-NB-3(CDDP). Valproic acid also reverted enhanced adhesion properties of drug-resistant UKF-NB-2, UKF-NB-6 and SKNSH cells, and therefore may provide an alternative approach to the treatment of drug-resistant NB by blocking invasive processes.
authors.affiliation: Zentrum der Chirurgie, Klinik für Urologie und Kinderurologie, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: R A
authors.initials: RA
authors.lastname: Blaheta
authors.forename: M
authors.initials: M
authors.lastname: Michaelis
authors.forename: I
authors.initials: I
authors.lastname: Natsheh
authors.forename: C
authors.initials: C
authors.lastname: Hasenberg
authors.forename: E
authors.initials: E
authors.lastname: Weich
authors.forename: B
authors.initials: B
authors.lastname: Relja
authors.forename: D
authors.initials: D
authors.lastname: Jonas
authors.forename: H W
authors.initials: HW
authors.lastname: Doerr
authors.forename: J
authors.initials: J
authors.lastname: Cinatl
mesh_terms: D000954:Antigens, Surface / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009361:Neoplasm Invasiveness; D019006:Neural Cell Adhesion Molecules / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology*
chemical_list: D000954:Antigens, Surface; D000970:Antineoplastic Agents; D019006:Neural Cell Adhesion Molecules; D012333:RNA, Messenger; D014750:Vincristine; D014635:Valproic Acid; D002945:Cisplatin