Abstract
BackgroundIn search of a suitable GSH-depleting agent, a novel copper complex viz., copper N-(2-hydroxyacetophenone) glycinate (CuNG) has been synthesized, which was initially found to be a potential resistance modifying agent and later found to be an immunomodulator in mice model in different doses. The objective of the present work was to decipher the effect of CuNG on reactive oxygen species (ROS) generation and antioxidant enzymes in normal and doxorubicin-resistant Ehrlich ascites carcinoma (EAC/Dox)-bearing Swiss albino mice.MethodsThe effect of CuNG has been studied on ROS generation, multidrug resistance-associated protein1 (MRP1) expression and on activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx).ResultsCuNG increased ROS generation and reduced MRP1 expression in EAC/Dox cells while only temporarily depleted glutathione (GSH) within 2 h in heart, kidney, liver and lung of EAC/Dox bearing mice, which were restored within 24 h. The level of liver Cu was observed to be inversely proportional to the level of GSH. Moreover, CuNG modulated SOD, CAT and GPx in different organs and thereby reduced oxidative stress. Thus nontoxic dose of CuNG may be utilized to reduce MRP1 expression and thus sensitize EAC/Dox cells to standard chemotherapy. Moreover, CuNG modulated SOD, CAT and and GPx activities to reduce oxidative stress in some vital organs of EAC/Dox bearing mice. CuNG treatment also helped to recover liver and renal function in EAC/Dox bearing mice.ConclusionBased on our studies, we conclude that CuNG may be a promising candidate to sensitize drug resistant cancers in the clinic.
Highlights
In search of a suitable GSH-depleting agent, a novel copper complex viz., copper N-(2hydroxyacetophenone) glycinate (CuNG) has been synthesized, which was initially found to be a potential resistance modifying agent and later found to be an immunomodulator in mice model in different doses
Since we have shown earlier that CuNG is a good resistance modifier [16] and as copper has been reported to induce apoptosis by generation of reactive oxygen species (ROS) [18], we tested whether CuNG treatment in vivo could increase ROS generation in EAC/Dox cells
CuNG treatment in vivo was found to induce ROS generation in EAC/ Dox cells by both Nitro Blue Tetrazolium (NBT) reduction (Fig. 1B) [>90% of the NBT reduction was inhibitable by superoxide dismutase (SOD)] as well as with H2O2 trapping dye, Dichlorofluoresceindiacetetate (DCF-DA) and Cytochrome c reduction
Summary
In search of a suitable GSH-depleting agent, a novel copper complex viz., copper N-(2hydroxyacetophenone) glycinate (CuNG) has been synthesized, which was initially found to be a potential resistance modifying agent and later found to be an immunomodulator in mice model in different doses. The objective of the present work was to decipher the effect of CuNG on reactive oxygen species (ROS) generation and antioxidant enzymes in normal and doxorubicin-resistant Ehrlich ascites carcinoma (EAC/ Dox)-bearing Swiss albino mice. The involvement of reactive oxygen species (ROS) in induction of apoptosis of various cancer cells, especially drug resistant cancers is well known [2,3,4]. Drug resistant cancers often show very low levels of ROS. This is usually due to high intracellular reduced glutathione (GSH) levels [7,8] and enhanced activities of antioxidant enzymes like glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD) [9]. High levels of GSH and GST have been implicated in drug resistant tumors [8,11,12]
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