EFFECT OF METAL IONS ON FUNCTIONING OF ANTIOXIDANT SYSTEM AND ENZYMES OF EXTRACELLULAR MATRIX IN TUMORS DIFFERED IN THEIR DOXORUBICIN SENSITIVITY
Yu.V. Lozovska1, N.Yu. Lukianova1, I.M. Andrusishyna2, I.M. Todor1, A.P. Burlaka1, I.I. Ganusevych1, V.F. Chekhun1
- R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAN of Ukraine, Ukraine
- SI 'Kundiiev Institute of Occupational Health, NAMN of Ukraine', Kyiv, Ukraine
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
macro- and microelements; Walker 256 carcinosarcoma; metallothionein-1; ceruloplasmin, ferritin, transferrin, myeloperoxidase, matrix metalloproteinases.
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