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; Michael V Talabaev; Stanislav P Urazov; Sergei G Shcherbak; Alessandra Renieri; Elisa Frullanti; Olga Shamova

doi:10.1515/dmdi-2020-0109

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

Drug Metab Pers Ther. 2020 Sep 16:/j/dmdi.ahead-of-print/dmdi-2020-0109/dmdi-2020-0109.xml. doi: 10.1515/dmdi-2020-0109. Online ahead of print.

Authors

Affiliations

¹ Department of Clinics and Genetics Investigations, Saint Petersburg City Hospital No40 of Resort District, Saint Petersburg, Russian Federation.
² Laboratory of Design and Synthesis of Biologically Active Peptides, Department of General Pathology and Pathophysiology, Institute of Experimental Medicine, Saint-Petersburg, Russian Federation.
³ Medical Genetics, Department of Medical Biotechnologies, University of Siena, Siena, Italy.
⁴ Department of Pediatric Neurosurgery, Republican Center for Neurology and Neurosurgery, Minsk, The Republic of Belarus.
⁵ Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.

PMID: 32887179
DOI: 10.1515/dmdi-2020-0109

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).

Keywords: MYCC-; MYCN-oncogenes; Trka; chemotherapy; nerve growth factor (NGF); p75 receptors.