DXR is an anthracene-derived drug. Antioxidants have been shown to have a protective effect against oxidative damage induced by antineoplastics, like doxorubicin
13,15. CoQ
10 is an endogenous lipophilic antioxidant, and is a key component for mitochondrial electron transport. CoQ
10 is used to treat oxidative damages and disorders that occur due to suboptimal metabolism of cellular energy
2. Vitamin E forms the first line of defense to protect the unsaturated fatty acids in the cell membrane against oxidation with free radicals
16.
In various studies conducted on this subject, MDA levels have been reported to increase in DXR-treated rats 17-20. In a study conducted on the heart tissues of rats, the researchers reported that the levels of MDA in the tissues of rats treated with DXR were higher than all other groups' and that the effects of CoQ10 and L-carnitine reduced the effects DXR 21. In a study conducted on rabbits, it was found that DXR treatment caused statistically significant increases in MDA levels, an end product of lipid peroxidation. The mean MDA values displayed significant increases at days 3, 4, 5 and 6 in the group treated with DXR+L-carnitine, compared to pre-treatment levels and the levels obtained at the 1st and 2nd day of the treatment. In the group treated only with L-carnitine, on the other hand, significant decreases were observed in mean MDA levels, compared to the pre-treatment period 22. In many studies, researchers reported that CoQ10 had protective effects against the toxic effects of doxorubicin 23-25 and CoQ10 has been shown to have protective properties against toxic effects of doxorubicin in testicular 26, kidney 27 and heart tissues 28,29.
Antineoplastic agents used in cancer patients undergoing chemotherapy cause oxidative stress 30. Doxorubicin was used to create cytotoxicity in lung tumor cells, and it has been reported by researchers that CoQ10 alone was not enough to reduce the effects of doxorubicin 24. The oxidative stress is manifested as increased lipid peroxidation products, and reduction of compounds with antioxidant properties in plasma such as Vitamins E and C and β-carotene, and glutathione.
Similar to the previous reports, serum MDA levels significantly increased in the groups treated with doxorubicin when compared to the control group in our study. Serum MDA levels of the DXR+CoQ10 and DXR+Vitamin E groups were lower compared to the DXR group but it was the lowest in the DXR+CoQ10 group.
Reduced GSH, a cytoplasmic antioxidant, plays an important role in cellular defense mechanisms against damage induced by lipid peroxidation. Mitochondrial GSH plays a critical role in cellular life and regulation of conditions caused by sulphydryl groups and resulting in decreased permeability in mitochondrial membranes 3.
Karapehlivan et al. 22 have found out that GSH levels of rabbits treated with DXR decreased significantly beginning from the third day of the treatment compared to the starting point, no significant change occurred in the group treated with DXR+L-carnitine, and that it increased significantly from the second day of the treatment in the group treated with L-carnitine alone. In another study, it was reported that GSH values in DXR group decreased compared to control 20.
In our study, GSH levels in all experimental groups were found to be below that of the control group. GSH value in DXR + CoQ10 group was found to be higher than DXR group.
In a study conducted at the cellular level, it was reported that CoQ10 and lutein had a protective effect against the oxidative damage of DXR and Etoposide as a result of SOD, GPx, ROS, and LPO tests 31.
Ceruloplasmin, mainly synthesized in the liver, is an acute phase protein that exhibits a moderate response in conditions such as inflammation and tissue damage 32.
Yu 33 reported that increase of ceruloplasmin take place depending on the lipid peroxidation in the cells. The results of the present study is in parallel with the study of Yu 33 as the ceruloplasmin levels were increased. In our study, ceruloplasmin levels were higher in all groups than that of the control group (P<0.001). However, ceruloplasmin levels were higher in DXR + vitamin E group than DXR group. The increase in the amount of ceruloplasmin in the vitamin E group might indicate that vitamin E has positive contributions to the prevention of lipid peroxidation.
Numerous studies report that Vitamins C, A, and E have antioxidant properties and reduce the peroxidation products or have supplementary effects for antineoplastic agents 3,34-36. Shinozawa et al 37 observed a slight increase in the survival periods of rats treated with 100 mg/kg/day alpha-tocopherol acetate before the doxorubicin treatment, but in contrast, they also observed a significant decrease in their survival periods when treated with 500 mg/kg/day alpha-tocopherol acetate. Myers et al. 38 have observed that administration of tocopherol significantly reduced the doxorubicin-caused cardiomyopathies. Another study reports that increased doses of Vitamin E treatment could have protective effects against doxorubicin-induced cardiac toxicities 39. In the present study, it was observed that retinol levels increased in CoQ10 groups when compared to DXR groups and α-tocopherol levels decreased in all DXR groups. However, these changes were not statistically significant.
Albumin is known to be a stronger anti-oxidant compared to globulin, due to its molecular structure 40 Albumin has the capability of scavengering hydroxyl radicals 41. In a previous study, serum albumin levels were reported to be low in pemphigus vulgaris patients 42. Oxidative stress and low antioxidant status in myasthenia gravis (MG) patients have been reported to also have significantly decreased in serum albumin levels 43. In rats experimentally induced sepsis, the albumin treatment had a 25% antioxidant effect on free radicals 44. In this study, albumin levels decreased in DXR, DXR+CoQ10 (P<0.05) and DXR +VitE groups. It increased in the CoQ10 group.
Afsar et al. 45, in their study, observed that the albumin level decreased in rats given DXR and that A. hydaspica polyphenol-rich ethyl acetate extract (AHE) given as a preservative increased the albumin level. Again, in this study, they reported that globulin levels decreased in rats given DXR and that AHE given as a preservative increased globulin levels.
In this study, the globulin levels increased significantly in all groups compared to the control group (P<0.001). In this study, total protein levels showed significant increases in DXR (P<0.001), CoQ10 (P<0.05), DXR+ CoQ10 (P<0.05) and DXR+VitE (P<0.001) groups.
Afsar et al. 45 reported in their study that the total protein level decreased in rats given DXR and increased in groups given AHE.
For all the experiment groups in the study, glucose levels were found to have decreased. Some studies report that oxidative stress can cause hyperglycemia 46,
In our study, ALT levels increased in DXR group compared to control group (P<0.001) and it was lower in DXR + CoQ10 and DXR + Vit E groups (P<0.05). Vitamin E and CoQ10 were found to have a protective effect against DXR by lowering ALT levels.
In all experiment groups, MDA levels were found to have increased while GSH levels were significantly decreased. Elevations in ceruloplasmin levels were observed. In the study, especially glucose levels decreased in all groups. It was observed that CoQ10 alone slightly increased this value, but CoQ10 and vitamin E did not show any effect in the groups with DXR.
In similar studies, it has been seen that antioxidant effective substances are successful against the effects of DXR. In our study, however, CoQ10 and Vit E did not show a curative effect at the desired level. The probable reason for this is estimated to be the length of the working time. The length of the period increased the stress factor and caused the expected improvements not to be seen. However, this study also reveals that prolonging the use of oxidant agents such as DXR will reduce the curative effects of antioxidant agents.
In conclusion, the results obtained in this study may suggest that various medication used in the treatment of cancer and some other diseases cause a variety of oxidative damages, and use of anti-oxidants could have favorable results in such cases.
Acknowledgments
The authors would like to thank Okan ARIHAN for his assistance in the writing process.
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