Expression of glutathione, glutathione peroxidase and glutathione S-transferase pi in canine mammary tumors

Abstract

BackgroundGlutathione (GSH) is one of the most important agents of the antioxidant defense system of the cell because, in conjunction with the enzymes glutathione peroxidase (GSH-Px) and glutathione S transferase pi (GSTpi), it plays a central role in the detoxification and biotransformation of chemotherapeutic drugs. This study evaluated the expression of GSH and the GSH-Px and GSTpi enzymes by immunohistochemistry in 30 canine mammary tumors, relating the clinicopathological parameters, clinical outcome and survival of the bitches. In an in vitro study, the expression of the genes glutamate cysteine ligase (GCLC) and glutathione synthetase (GSS) that synthesize GSH and GSH-Px gene were verified by qPCR and subjected to treatment with doxorubicin, to check the resistance of cancer cells to chemotherapy.ResultsThe immunohistochemical expression of GSH, GSH-Px and GSTpi was compared with the clinical and pathological characteristics and the clinical outcome in the bitches, including metastasis and death.The results showed that high immunoexpression of GSH was correlated to the absence of tumor ulceration and was present in dogs without metastasis (P < 0.05). There was significant correlation of survival with the increase of GSH (P < 0.05). The expression of the GSH-Px and GSTpi enzymes showed no statistically significant correlation with the analyzed variables (p > 0.05). The analysis of the relative expression of genes responsible for the synthesis of GSH (GCLC and GSS) and GSH-Px by quantitative PCR was done with cultured cells of 10 tumor fragments from dogs with mammary tumors.The culture cells showed a decrease in GCLC and GSS expression when compared with no treated cells (P < 0.05). High GSH immunoexpression was associated with better clinical outcomes.ConclusionTherefore, high expression of the GSH seems to play an important role in the clinical outcome of patients with mammary tumors and suggest its use as prognostic marker. The in vitro doxorubicin treatment significantly reduces the expression of GCLC and GSS genes so we can consider them to be candidates for predictive markers of therapeutic response in mammary cancer.

Involvement of glutathione and glutathione metabolizing enzymes in human colorectal cancer cell lines and tissues

“…Previous studies have reported that the expression levels of GSH are elevated in numerous types of human cancer tissue, and increased expression levels of GCLC have also been identified in lung, breast, liver, and other types of cancer (19,20). In addition, GCLC and GSS were highly expressed in the mammary tumors and can be used as prognostic markers for mammary neoplasm (21). Furthermore, a previous study demonstrated that drug-resistance is associated not only with elevated GSH levels, but also with increased activity of GCLC (22).…”

Altered oxidative stress and carbohydrate metabolism in canine mammary tumors

“…[22] reported no significant difference in serum thiol groups in dogs with and without mammary tumor. Increased GSH expression is reported in canine mammary tumors without ulceration, not metastatic tumors, and low mortality [25]. Intracellular GSH maintains the reduced status of thioredoxin which activates ribonucleotide reductase, a key enzyme essential for DNA synthesis [1].…”

Global metabolomics profiling of colorectal cancer in Malaysian patients

“…38 Elevated GSH levels have been observed in numerous types of human cancer tissues and increased glutamate-cysteine ligase catalytic activity (GCLC) have also been reported in lung, breast, liver, and other types of cancer. 44 GCLC and GSH synthetase are enzymes in GSH metabolism and their levels were reported to be elevated in CRC tissues. 42 Hence increased GSH metabolism may indicate increased oxidative status in cancer cells due to increased energy metabolism.…”