The efficiency of cisplatin (CDDP) is significantly hindered by the development of resistance during the treatment course. To gain a detailed understanding of the molecular mechanisms underlying the development of cisplatin resistance, we comparatively analyzed established a CDDP-resistant neuroblastoma cell line (UKF-NB-4CDDP) and its susceptible parental cells (UKF-NB-4). We verified increased chemoresistance of UKF-NB-4CDDP cells by analyzing the viability, induction of apoptosis and clonal efficiency. To shed more light on this phenomenon, we employed custom cDNA microarray (containing 2234 probes) to perform parallel transcriptomic profiling of RNA and identified that 139 genes were significantly up-regulated due to CDDP chemoresistance. The analyses of molecular pathways indicated that the top up-regulation scoring functions were response to stress, abiotic stimulus, regulation of metabolic process, apoptotic processes, regulation of cell proliferation, DNA repair or regulation of catalytic activity, which was also evidenced by analysis of molecular functions revealing up-regulation of genes encoding several proteins with a wide-spectrum of enzymatic activities. Functional analysis using lysosomotropic agents chloroquine and bafilomycin A1 validated their potential to re-sensitize UKF-NB-4CDDP cells to CDDP. Taken together, the identification of alterations in specific genes and pathways that contribute to CDDP chemoresistance may potentially lead to a renewed interest in the development of novel rational therapeutics and prognostic biomarkers for the management of CDDP-resistant neuroblastoma.

• Klíčová slova
• chemoresistance, cisplatin, lysosomes, microarray, neuroblastoma, transport,
• MeSH
• buněčné klony MeSH
• chemorezistence účinky léků   genetika   MeSH
• chlorochin farmakologie   MeSH
• cisplatina farmakologie   terapeutické užití   MeSH
• genová ontologie MeSH
• genové regulační sítě účinky léků   MeSH
• lidé MeSH
• lyzozomy účinky léků   metabolismus   MeSH
• makrolidy farmakologie   MeSH
• nádorové buněčné linie MeSH
• neuroblastom farmakoterapie   genetika   patologie   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• transkriptom účinky léků   genetika   MeSH
• tvar buňky účinky léků   MeSH
• upregulace účinky léků   genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• bafilomycin A1 MeSH Prohlížeč
• chlorochin MeSH
• cisplatina MeSH
• makrolidy MeSH