Tomas Eckschlager

Chemoresistance is a major cause of cancer therapy failure. Increasing evidence points to the importance of histone lysine demethylase function, whose dysregulation has been described in several types of cancer. KDM5, a family of histone lysine demethylases, may carry out a key role in the downregulation of tumor-suppressors or upregulation of oncogenes and in the development of drug tolerance. The present study examined the expression of KDM5D in cell lines derived from high-risk neuroblastoma. The present study found that KDM5D expression was lost in all cisplatin-chemoresistant neuroblastoma cell lines compared with sensitive parental cells. In addition, the cisplatin-chemoresistant neuroblastoma cell line had increased expression of the ubiquitin ligase cullinaA 4A (CUL4A) compared with the sensitive parental cells. CUL4A carries out a role in cellular processes and its aberrant regulation has been observed in a number of types of cancer. The present study shows that silencing of KDM5D causes a more aggressive phenotype of neuroblastoma by promoting cell proliferation and migration, evading cell death, promoting S phase of the cell cycle and desensitizing sensitive cells to cisplatin via the gene CUL4A. In addition, ectopic expression of KMD5D in a cisplatin-resistant cell line reversed these phenomena. The results suggest that KDM5D and/or CUL4A may be a biomarkers of chemoresistance to cisplatin and a potential therapeutic target in neuroblastoma.

Drug resistance remains a major obstacle in neuroblastoma treatment. Lysosomal sequestration, facilitated by the V-ATPase proton pump, is one of the mechanisms of chemoresistance. Overexpression of the ATP6V0D1 subunit of V-ATPase, previously reported in various cancers, was also observed in ellipticine-resistant neuroblastoma cells in our study. Neuroblastoma cells also exhibited increased lysosomal capacity and vacuolation after ellipticine treatment. Knockdown of ATP6V0D1, but not ATP6V1H, enhanced ellipticine sensitivity, suppressed proliferation and migration, decreased lysosomal uptake, and induced G2/M arrest in neuroblastoma cell lines. Notably, inhibiting another V-ATPase subunit, ATP6V1H, had no effect, highlighting the specific role of ATP6V0D1 in drug resistance. Ellipticine-induced vacuolation, identified as endoplasmic reticulum swelling, lacked evidence of paraptosis. ATP6V0D1 knockdown suppressed this phenomenon, whereas ATP6V1H silencing did not. Our findings underscore the importance of ATP6V0D1 in neuroblastoma and suggest potential therapeutic strategies targeting V-ATPase for overcoming drug resistance.

Chemoresistance is a major cause of cancer therapy failure. Increasing evidence points to the importance of histone lysine demethylase function, whose dysregulation has been described in many cancers. KDM5, a family of histone lysine demethylases, may play a critical role in downregulation of tumour-suppressors or upregulation of oncogenes and in the development of drug tolerance. In this study, we examined the expression of KDM5D in cell lines derived from high-risk neuroblastoma. We found that KDM5D expression was lost in all cisplatin-chemoresistant neuroblastoma cell lines compared with sensitive parental cells. In addition, we found that the cisplatin-chemoresistant neuroblastoma cell line had increased expression of the ubiquitin ligase cullin 4A (CUL4A) compared with the sensitive parental cells. CUL4A plays a role in cellular processes and its aberrant regulation has been observed in a number of cancers. We have shown that silencing of KDM5D causes a more aggressive phenotype of NBL by promoting cell proliferation and migration, evading cell death, promoting S phase of the cell cycle, and desensitizing sensitive cells to CDDP via the gene CUL4A. In addition, ectopic expression of KMD5D in a cisplatin-resistant cell line reversed these phenomena. Our results suggest that KDM5D and / or CUL4A may be a biomarkers of chemoresistance to cisplatin and a potential therapeutic target in NBL.

Progress in medicine has increased the survival time of children suffering from cancer; >80% of patients survive for at least 5 years from the end of treatment. However, there are late effects of anticancer therapy, which accompany this success. Two‑thirds of childhood cancer survivors (CCSs) have at least one late effect (any side effects or complications of anticancer treatment that appear months to years after the completion of treatment), e.g. endocrinopathies, cardiovascular diseases or subsequent cancers, and half of these late effects are serious or life threatening. These late consequences of childhood cancer treatment pose a serious health, social and economic problem. A common mechanism for developing a number of late effects is the onset of premature biological aging, which is associated with the early onset of chronic diseases and death. Cellular senescence in cancer survivors is caused by therapy that can induce chromosomal aberrations, mutations, telomere shortening, epigenetic alterations and mitochondrial dysfunctions. The mechanisms of accelerated aging in cancer survivors have not yet been fully clarified. The measurement of biological age in survivors can help improve the understanding of aging mechanisms and identify risk factors for premature aging. However, to the best of our knowledge, no single marker for the evaluation of biological or functional age is known, so it is therefore necessary to measure the consequences of anticancer treatment using complex assessments. The present review presents an overview of premature aging in CCSs and of the mechanisms involved in its development, focusing on the association of senescence and late effects.

Chemoresistance is a major problem in successful cancer therapy. Lysine‑specific demethylase 5B (KDM5B), is a member of the KDM5 family of histone demethylases, whose dysregulation has been observed in numerous types of cancer and plays a role in drug tolerance. The present study examined KDM5B expression in high risk neuroblastoma cell lines. Its level was markedly reduced in cisplatin‑resistant cells, UKF‑NB‑4^CDDP, compared with parental sensitive cells UKF‑NB‑4. Moreover, KDM5B‑silencing did not affect either viability nor the response to CDDP in resistant cells, and led to increase of proliferation and migration in CDDP resistant cells but not in sensitive ones. Compliant with these results, short interfering KDM5B transfection resulted in increased S phase in resistant cells. Overall, these findings suggested that KDM5B may be involved in the survival mechanisms of neuroblastoma cells, which makes KDM5B a promising factor for the prediction of sensitivity to CDDP that should therefore be considered for future research.

Advances in medicine have improved outcomes in children diagnosed with cancer, with overall 5-year survival rates for these children now exceeding 80%. Two-thirds of childhood cancer survivors have at least one late effect of cancer therapy, with one-third having serious or even life-threatening effects. One of the most serious late effects is a development of subsequent malignant neoplasms (histologically different cancers, which appear after the treatment for primary cancer), which occur in about 3–10% of survivors and are associated with high mortality. In cancers with a very good prognosis, subsequent malignant neoplasms significantly affect long-term survival. Therefore, there is an effort to reduce particularly hazardous treatments. This review discusses the importance of individual factors (gender, genetic factors, cytostatic drugs, radiotherapy) in the development of subsequent malignant neoplasms and the possibilities of their prediction and prevention in the future.

A tyrosine kinase inhibitor, vandetanib (Van), is an anticancer drug affecting the signaling of VEGFR, EGFR and RET protooncogenes. Van is primarily used for the treatment of advanced or metastatic medullary thyroid cancer; however, its usage is significantly limited by side effects, particularly cardiotoxicity. One approach to minimize them is the encapsulation or binding of Van in- or onto a suitable carrier, allowing targeted delivery to tumor tissue. Herein, we constructed a nanocarrier based on apoferritin associated with Van (ApoVan). Based on the characteristics obtained by analyzing the average size, the surface ζ-potential and the polydispersive index, ApoVan nanoparticles exhibit long-term stability and maintain their morphology. Experiments have shown that ApoVan complex is relatively stable during storage. It was found that Van is gradually released from its ApoVan form into the neutral environment (pH 7.4) as well as into the acidic environment (pH 6.5). The effect of free Van and ApoVan on neuroblastoma and medullary thyroid carcinoma cell lines revealed that both forms were toxic in both used cell lines, and minimal differences between ApoVan and Van were observed. Thus, we assume that Van might not be encapsulated into the cavity of apoferritin, but instead only binds to its surface.