Effect of Metal Ions on Functioning of Antioxidant System and Enzymes of Extracellular Matrix in Tumors Differed in Their Doxorubicin Sensitivity

Abstract

The content of the essential macro- and microelements (MaE and ME) – copper, zinc, magnesium, iron and calcium was measured in blood plasma (BP) and tumor tissue (TT) of the animals engrafted with Walker 256 carcinosarcoma (tumor strains sensitive or resistant to doxorubicin). Also, the link between the content of these elements and the functional state of metal-containing enzymes of antioxidant system (metallothionein-1 – MT-1, ceruloplasmin – CP, ferritin – FR, myeloperoxidase – MPO, transferrin – TF) as well proteolytic enzymes (matrix metalloproteinases – MMP-2 and -9) was studied. In BP of animals engrafted with either sensitive or resistant to doxorubicin carcinosarcoma Cu/Zn and Ca/Mg ratios increase 2.8-fold and 1.4-fold, respectively as compared to the intact animals. The differences between MaE and ME content in the animals with tumors differed in doxorubicin sensitivity as compared to the intact animals affected the indices of prooxidant-antioxidant system: 2.7 and 1.6-fold increase of MT-1 (for sensitive and resistant tumors, correspondingly), 1.2 and 1.6-fold increase of CP, and 4.6- and 9-fold increase of FR against 5 and 7.5-fold decrease of MPO and 1.3 and 1.9-fold decrease in TF. In TT of the animals engrafted with the resistant strain 1.7-fold decrease of MT-1, 65-fold increase of FR, and 2.5-fold increase of TF was evident as compared with TT of animals engrafted with the sensitive strain. The change in prooxidant-antioxidant balance in tumorbearing animals was accompanied by the increased proteolytic activity of the enzymes involved in remodeling extracellular matrix, MMP-2 and MMP-8. Increased copper and iron content in BP and TT of the animals with doxorubicinresistant Walker 256 carcinosarcoma could initiate of freeradical compounds generation and enhancement of MMP-2 and MMP-9 activation. Therefore, the ionic misbalance might be the cause of changes of the antioxidant system functions contributing to the formation of the resistant phenotype of neoplasms. This provides the rationale for the use of chelating agents for increasing sensitivity of resistant neoplasms to cytostatics.