Resistance to chemotherapeutics and targeted drugs is one of the main problems in successful cancer therapy. Various mechanisms have been identified to contribute to drug resistance. One of those mechanisms is lysosome-mediated drug resistance. Lysosomes have been shown to trap certain hydrophobic weak base chemotherapeutics, as well as some tyrosine kinase inhibitors, thereby being sequestered away from their intracellular target site. Lysosomal sequestration is in most cases followed by the release of their content from the cell by exocytosis. Lysosomal accumulation of anticancer drugs is caused mainly by ion-trapping, but active transport of certain drugs into lysosomes was also described. Lysosomal low pH, which is necessary for ion-trapping is achieved by the activity of the V-ATPase. This sequestration can be successfully inhibited by lysosomotropic agents and V-ATPase inhibitors in experimental conditions. Clinical trials have been performed only with lysosomotropic drug chloroquine and their results were less successful. The aim of this review is to give an overview of lysosomal sequestration and expression of acidifying enzymes as yet not well known mechanism of cancer cell chemoresistance and about possibilities how to overcome this form of resistance.

Cisplatin (CDDP) is a widely used agent in the treatment of neuroblastoma. Unfortunately, the development of acquired chemoresistance limits its clinical use. To gain a detailed understanding of the mechanisms underlying the development of such chemoresistance, we comparatively analysed established cisplatin-resistant neuroblastoma cell line (UKF-NB-4 CDDP) and its sensitive counterpart (UKF-NB-4). First, using viability screenings, we confirmed the decreased sensitivity of tested cells to cisplatin and identified a cross-resistance to carboplatin and oxaliplatin. Then, the proteomic signatures were analysed using nanoLC MS/MS. Among the proteins responsible for UKF-NB-4 CDDP chemoresistance, ion channels transport family proteins, ABC superfamily proteins, SLC-mediated trans-membrane transporters, proteasome complex subunits and V-ATPases were identified. Moreover, we detected markedly higher proteasome activity in UKF-NB-4 CDDP cells and a remarkable lysosomal enrichment that can be inhibited by bafilomycin A to sensitize UKF-NB-4 CDDP to CDDP. Our results indicate that lysosomal sequestration and proteasome activity may be one of key mechanisms responsible for intrinsic chemoresistance of neuroblastoma to CDDP.

Intracranial ependymoma represents one of the most common pediatric central nervous system malignancies, and exhibits a wide range of clinical behavior from relatively indolent lesions to highly malignant anaplastic ependymomas. Due to the heterogeneous nature of this disease there is lack of prognostic markers, which would reliably predict the outcome of patients. MicroRNAs (miRNAs) have emerged as important molecules in cancer biology during past decade; however, very little is known about their role in ependymomas. The aim of the present study was to evaluate expression of miRNAs in archived formalin-fixed paraffin-embedded (FFPE) samples of pediatric intracranial ependymomas. The expression of miRNAs were examined in 29 samples of ependymoma and we observed that miR-135a-3p, miR-137, miR-17-5p, miR-181d and let-7d-5p were upregulated. In addition, a significantly higher expression of miR-203a was detected in Grade III tumors suggesting its possible use as a prognostic or diagnostic marker. The present study also demonstrated that storage of (FFPE) ependymoma samples for >20 years did not result in a deterioration of miRNAs. The present findings broaden the presently available knowledge regarding miRNA expression in ependymomas and provide further evidence for the employment of miRNA analysis as a supplementary method for the morphological assessment of ependymoma samples. Materials and methods Patients and samples. A total of 29 formalin-fixed paraffin-embedded (FFPE) specimens of ependymomas were collected retrospectively from the archives of