TITLE:
Manifestation of Key Molecular Genetic Markers in Pharmacocorrection of Endogenous Iron Metabolism in MCF-7 and MCF-7/DDP Human Breast Cancer Cells
AUTHORS:
Vasyl’ Chekhun, Natalia Lukianova, Dmytro Demash, Tetiana Borikun, Svyatoslav Chekhun, Yulia Shvets
KEYWORDS:
Nanocomposite; Iron Metabolism; Apoptosis; ROS; Drug Resistance; Breast Cancer Cells
JOURNAL NAME:
CellBio,
Vol.2 No.4,
December
4,
2013
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.