Abstract

Introduction. Chemotherapy is an extremely ineffective and unsatisfactory means of treating malignant melanoma due to drug resistance, which is characteristic of this disease. A number of studies have shown that liposomal forms of anticancer drugs are able to overcome the multidrug resistance, but the mechanism by which this occurs is still remained to be elucidated. Aranoza (DNA-alkylating agent, a derivative of nitrosourea) has been approved for the treatment of patients with metastatic melanoma. Objective: to examine the influence of liposomal aranoza as well as the empty liposomes and “liophilisate for the preparation of solution for injections” (aranoza-lio) on the expression of mRNA of p53, MDM2, NFkB1, NFkB2, MyD88. Materials and methods. The study was performed with 10 melanoma cell lines, 4 of which carried the BRAF mutation. The level of p53, MDM2, NFkB1, NFkB2, MyD88 mRNA was investigated by quantitative polymerase chain reaction in real time. Results. Aranoza-lio increased slightly the expression of p53 mRNA in BRAF-mutated cells. We have observed also the increased expression of MDM2 mRNA (p = 0.0013). The expression of NFkB2, MyD88 mRNA did not change significantly as compared to control. Liposomal aranoza increased the expression of NFkB1 mRNA. Conclusion. Based on the data obtained we conclude that the liposomal aranoza triggers the mechanisms that contribute to sensitivity of cells toward anticancer drugs while aranoza-lio favored the enhancing of the expression of MDM2 mRNA and increase the resistance to chemotherapy.

Highlights

  • Chemotherapy is an extremely ineffective and unsatisfactory means of treating malignant melanoma due to drug resistance, which is characteristic of this disease

  • The study was performed with 10 melanoma cell lines, 4 of which carried the BRAF mutation

  • The level of p53, MDM2, NFkB1, NFkB2, MyD88 mRNA was investigated by quantitative polymerase chain reaction in real time

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Summary

Оригинальные статьи

Цель исследования – изучить воздействие лекарственных форм аранозы (липосомальной и «лиофилизата для приготовления раствора для инъекций» (араноза-лио)), а также пустых липосом на экспрессию мРНК р53, MDM2, NFkB1, NFkB2, MyD88 в опухолевых клетках. Араноза-лио повышает экспрессию мРНК р53 незначительно и только на BRAF-положительных клетках, при этом статистически значимо (p = 0,0013) повышает экспрессию мРНК MDM2 – фактора резистентности опухоли к химиотерапии. Липосомальная араноза повышает экспрессию мРНК NFkB1 – фактора гибели клеток в ответ на повреждение ДНК метилированием. Две лекарственные формы аранозы – липосомальная и араноза-лио – оказывают различное воздействие на внутриклеточные сигнальные пути в клетках метастатической меланомы. Араноза-лио запускает механизмы устойчивости к химиотерапии посредством повышения экспрессии мРНК MDM2. Липосомальная араноза, наоборот, запускает механизмы, способствующие чувствительности клеток к терапии, через повышение экспрессии мРНК NFkB1 – фактора гибели клеток в ответ на повреждение ДНК метилированием. Blokhin Russian Cancer Research Center, Ministry of Health of Russia; 24 Kashirskoe Shosse, Moscow 115478, Russia

Introduction
РОССИЙСКИЙ БИОТЕРАПЕВТИЧЕСКИЙ ЖУРНАЛ Russian journal of biotherapy
Findings
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