Abstract
The study was focused on the detection of changes in serum and tumor metal-containing proteins in animals during development ofdoxorubicin-resistant phenotype in malignant cells after 12 courses of chemotherapy. We found that on every stage of resistance development there was a significant increase in content of ferritin and transferrin proteins (which take part in iron traffick and storage) in Walker-256 carc'inosarcoma tissue. We observed decreased serumferritin levels at the beginning stage of the resistance development and significant elevation of this protein levels in the cases withfully developed resistance phenotype. Transferrin content showed changes opposite to that offerritin. During the development of resistance phenotype the tumor tissue also exhibited increased 'free iron' concentration that putatively correlate with elevation of ROS generation and levels of MMP-2 and MMP-9 active forms. The tumor non-protein thiol content increases gradually as well. The serum of animals with early stages of resistance phenotype development showed high ceruloplasmin activity and its significant reduction after loss of tumor sensitivity to doxorubicin. Therefore, the development of resistance phenotype in Walker-256 carcinosarcoma is accompanied by both the deregulation of metal-containing proteins in serum and tumor tissue and by the changes in activity of antioxidant defense system. Thus, the results of this study allow us to determine the spectrum of metal-containing proteins that are involved in the development of resistant tumor phenotype and that may be targeted for methods for doxorubicin sensitivity correction therapy.
Highlights
The topic of tumor-organism interaction persists as a crucial issue in modern clinical and experimental oncology
Due to all of the above, we aimed the present study to characterize the functional state of metalloproteins at tumor and organism levels during formation of Walker-256 carcinosarcoma doxorubicinresistant phenotype, namely that of transferrin, ferritin, ceruloplasmin and matrix metalloproteina ses 2 and 9 on in vivo models
It has been established that tumor locus formation followed by endogenous intoxication of organism leads to misbalancing in regulation of essential trace elements, including accumulation of ‘free iron’ (Fe2+)
Summary
The topic of tumor-organism interaction persists as a crucial issue in modern clinical and experimental oncology This is primarily due to the fact that no data has been presented as yet that would describe the totality of the complex rearrangements in tumor and organism that occur during tumor growth, beginning with the formation of primary locus and through to the active generalization. The latter is clearly related to another unsolved issue of the modern oncology – the tumor resistance to cytostatics. Due to all of the above, we aimed the present study to characterize the functional state of metalloproteins at tumor and organism levels during formation of Walker-256 carcinosarcoma doxorubicinresistant phenotype, namely that of transferrin, ferritin, ceruloplasmin and matrix metalloproteina ses 2 and 9 on in vivo models
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