Related expression of TRKA and P75 receptors and the changing copy number of MYC-oncogenes determine the sensitivity of brain tumor cells to the treatment of the nerve growth factor in combination with cisplatin and temozolomide
-
Alexandr N. Chernov
,
Diana A. Alaverdian
,
Oleg S. Glotov
Abstract
Objectives
Oncological diseases are an urgent medical and social problem. The chemotherapy induces not only the death of the tumor cells but also contributes to the development of their multidrug resistance and death of the healthy cells and tissues. In this regard, the search for the new pharmacological substances with anticancer activity against drug-resistant tumors is of utmost importance. In the present study we primarily investigated the correlation between the expression of TrkA and p75 receptors with the nerve growth factor (NGF) and cisplatin or temozolomide sensitivity of anaplastic astrocytoma (AA), glioblastoma (GB) and medulloblastoma (MB) cell cultures. We then evaluated the changing of copy numbers of MYCC and MYCN and its correlation with cytotoxicity index (CI) in MB cells under NGF exposition.
Methods
The primary cell cultures were obtained from the tumor biopsy samples of the patients with AA (n=5), GB (n=7) or MB (n=25) prior to radiotherapy and chemotherapy. The cytotoxicity effect of NGF and its combinations with cisplatin or temozolomide, the relative expression of TrkA and p75 receptors, its correlations with CI in AA, GB and MB primary cell cultures were studied by trypan blue cytotoxicity assay and immunofluorescence staining respectively. The effect of NGF on MYCC and MYCN copy numbers in MB cell cultures was studied by fluorescence in situ hybridization.
Results
We found that the expression of TrkA and p75 receptors (p=0.03) and its ratio (p=0.0004) depends on the sensitivity of AA and GB cells to treatment with NGF and its combinations with cisplatin or temozolomide. NGF reduces (p<0.05) the quantity of MB cells with six or eight copies of MYCN and three or eight copies of MYCC. Besides, NGF increases (p<0.05) the quantity of MB cells containing two copies of both oncogenes. The negative correlation (r=−0.65, p<0.0001) is established between MYCC average copy numbers and CI of NGF in MB cells.
Conclusions
The relative expression of NGF receptors (TrkA/p75) and its correlation with CI of NGF and its combinations in AA and GB cells point to the mechanism involving a cell death signaling pathway. NGF downregulates (p<0.05) some increased copy numbers of MYCC and MYCN in the human MB cell cultures, and upregulates normal two copies of both oncogenes (p<0.05).
Funding source: Belarusian Republican Foundation for Fundamental Research projects
Award Identifier / Grant number: Mechanisms for involving nerve growth factor in“Prognostic the value of amplification of MYCC
Funding source: National Academy of Sciences of Belarus for graduate students
Award Identifier / Grant number: Mechanisms for the separate and joint influence
Acknowledgments
The authors are grateful to professor Nataliya E. Konoplya and researcher Elena V. Volochnik, MD, researcher of Cytogenetics of the Republican Scientific and Practical Center for Pediatric Oncology, Hematology and Immunology (Republic of Belarus) for their help in conducting FISH analysis.
Research funding: Funding with the participation of Belarusian Republican Foundation for Fundamental Research projects: “Mechanisms for involving nerve growth factor in the in vitro oncogenesis process” (No. B10M−059 of 05.01.2010, State Registration No. 20101611) and “Prognostic the value of amplification of MYCC and MYCN oncogenes in human medulloblastomas ”(No. M13-091 of 04.16.2013, state registration No. 20131747); grant of the National Academy of Sciences of Belarus for graduate students “Mechanisms for the separate and joint influence of growth factors and cytostatics on medulloblastoma and glioma cells”.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest.
Informed consent: Informed consent was obtained from all individuals included in this study.
Ethical approval: The study was approved by the Ethics Committee at the Institute of Physiology of the National Academy of Sciences of Belarus in 12.05.2013, protocol No 1466.
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© 2020 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Editorial
- The need of the clinical implementation of pharmacogenetics in European health services for routine drug prescription. What’s next? An urgent clinical unmet need for patients
- Review
- Understanding COVID-19 in the light of epidemic disease described in Unani medicine
- Original Articles
- Pharmacogenetics of antipsychotics in adolescents with acute psychotic episode during first 14 days after admission: effectiveness and safety evaluation
- Using a pharmacogenetic clinical decision support system to improve psychopharmacotherapy dosing in patients with affective disorders
- A study of the pharmacokinetics of moxifloxacin by the dynamics of its distribution in the blood plasma and saliva of healthy volunteers: a comparative analysis and possible extrapolation methods
- Genotype-driven pharmacokinetic simulations of warfarin levels in Puerto Ricans
- Prognostic indicators in critically ill poisoned patients: development of a risk-prediction nomogram
- Related expression of TRKA and P75 receptors and the changing copy number of MYC-oncogenes determine the sensitivity of brain tumor cells to the treatment of the nerve growth factor in combination with cisplatin and temozolomide
- Genetic influence of DPYD*9A polymorphism on plasma levels of 5-fluorouracil and subsequent toxicity after oral administration of capecitabine in colorectal cancer patients of South Indian origin
- Methyl jasmonate delays the latency to anoxic convulsions by normalizing the brain levels of oxidative stress biomarkers and serum corticosterone contents in mice with repeated anoxic stress
- Diosmin attenuates schizophrenia-like behavior, oxidative stress, and acetylcholinesterase activity in mice
- Case Report
- NUDT15 polymorphism explains serious toxicity to azathioprine in Indian patients with chronic immune thrombocytopenia and autoimmune hemolytic anemia: a case series
Articles in the same Issue
- Editorial
- The need of the clinical implementation of pharmacogenetics in European health services for routine drug prescription. What’s next? An urgent clinical unmet need for patients
- Review
- Understanding COVID-19 in the light of epidemic disease described in Unani medicine
- Original Articles
- Pharmacogenetics of antipsychotics in adolescents with acute psychotic episode during first 14 days after admission: effectiveness and safety evaluation
- Using a pharmacogenetic clinical decision support system to improve psychopharmacotherapy dosing in patients with affective disorders
- A study of the pharmacokinetics of moxifloxacin by the dynamics of its distribution in the blood plasma and saliva of healthy volunteers: a comparative analysis and possible extrapolation methods
- Genotype-driven pharmacokinetic simulations of warfarin levels in Puerto Ricans
- Prognostic indicators in critically ill poisoned patients: development of a risk-prediction nomogram
- Related expression of TRKA and P75 receptors and the changing copy number of MYC-oncogenes determine the sensitivity of brain tumor cells to the treatment of the nerve growth factor in combination with cisplatin and temozolomide
- Genetic influence of DPYD*9A polymorphism on plasma levels of 5-fluorouracil and subsequent toxicity after oral administration of capecitabine in colorectal cancer patients of South Indian origin
- Methyl jasmonate delays the latency to anoxic convulsions by normalizing the brain levels of oxidative stress biomarkers and serum corticosterone contents in mice with repeated anoxic stress
- Diosmin attenuates schizophrenia-like behavior, oxidative stress, and acetylcholinesterase activity in mice
- Case Report
- NUDT15 polymorphism explains serious toxicity to azathioprine in Indian patients with chronic immune thrombocytopenia and autoimmune hemolytic anemia: a case series
