Manifestation of Key Molecular Genetic Markers in Pharmacocorrection of Endogenous Iron Metabolism in MCF-7 and MCF-7/DDP Human Breast Cancer Cells

Abstract

Effects of the nanocomposite and its components (magnetic fluid, cisplatin) on the level of endogenous iron exchange and the key links of genetic and epigenetic regulation of apoptotic program of sensitive and resistant MCF-7 cells were examined. We showed genetic and epigenetic mechanisms of action of nanocomposite of magnetic fluid and cisplatin. Nanocomposite caused elevation of number of cells in apoptosis in sensitive and especially resistant MCF-7 cells compared to cisplatin alone. It was proved that impact of nanocomposite on MCF-7/S and MCF-7/DDP cells caused more significant changes in expression of apoptosis regulators p53, Bcl-2 and Bax. We also suggested that changes in endogenous iron homeostasis and activation of free radical processes caused significant impact on apoptosis. Those changes included changes in methylation and expression of transferrin, its receptors, ferritin heavy and light chains (predominantly in resistant cell line), which caused activation of free radical synthesis and development of oxidative stress. We also showed that nanocomposite impact resulted into significant changes in expression of miRNA-34a and miRNA-200b, which regulated apoptosis, cell adhesion, invasion and activity of ferritin heavy chains gene. Thus, use of nanocomposite containing cisplatin and ferromagnetic as exogenous source of Fe ions caused changes of endogenous iron levels in sensitive and resistant cells allowing to increase specific activity of cytostatics and overcome factors, which promoted MDR development. Pharmacocorrection of endogenous iron metabolism allowed increasing antitumor activity of cisplatin and overcoming drug resistance.

Metalloproteins during development of Walker-256 carcinosarcoma resistant phenotype

“…Rapid decrease of blood serum Tr level and CP activity and corresponding increase in indices of metalloproteins and matrix metalloproteinases in tumor loci on the background of total doxorubicin insensitivity is a favorable condition for activation of proliferation and for development of malignant strain with enhanced invasiveness and metastasis potential [20].…”

Pharmacokinetics and Biological Effects of Ferromagnetic Nanocomposite in Rats with Sensitive and Ddp-Resistant Guerin’s Carcinoma

“…It has been established that during the development of cancer cells resistance the level of merging the Fe2+ -containing compounds increases significantly due to a significant increase in the level of transferrin and its receptors, as well as heavy and light ferritin chains [15]. This allowed us to begin the search for exogenous factors of DDPpharmacocorrection, as one of the most common drug in cancer patients chemotherapy [18,19]. Attracting nanotechnologies has made it possible to create a nanocomposite -a new medicine based on a conjugate ferromagnet and cisplatin (Feroplat ® ) [20].…”

Experimental study of the influence of recombinant human lactoferrin on the levels of androgens and basic parameters of lipid and protein metabolism

“…В рамках выполнения программы Союзного государства "БелРосТрансген-2" из молока трансгенных коз получен рекомбинантный лактоферрин человека (рчЛФ) [15,16] -один из основных белковых компонентов молока, негемовый железосвязывающий гликопротеин, относимый к семейству трансферринов. В наших условиях белок был выделен из молока с помощью катионообменной хроматографии (до 95-98% чистоты) и имел степень насыщения железом 10-20% [17].…”