What are Glutathione S Transferases (GSTs)?
Glutathione S Transferases (GSTs) are a family of enzymes that play a crucial role in the detoxification of endogenous and exogenous compounds. They catalyze the conjugation of the antioxidant molecule
glutathione to various substrates, facilitating their removal from the body. GSTs are involved in the metabolism of carcinogens, therapeutic drugs, and by-products of oxidative stress.
How are GSTs Related to Cancer?
GSTs have a dual role in cancer. On one hand, they protect cells from
oxidative damage and the toxic effects of environmental carcinogens. On the other hand, their overexpression can lead to resistance against chemotherapy drugs, making cancer treatment less effective. This dual nature makes GSTs a significant focus of cancer research.
What Types of GSTs Are There?
The GST family is divided into several classes, including Alpha, Mu, Pi, Theta, and Omega. Each class has its own specific functions and tissue distributions. For instance, GSTP1 (Pi class) is frequently overexpressed in various cancers and is associated with poor prognosis and
drug resistance.
How Do GSTs Contribute to Drug Resistance?
GSTs contribute to drug resistance by detoxifying chemotherapy agents before they can exert their cytotoxic effects on cancer cells. This is particularly problematic in treatments involving alkylating agents, anthracyclines, and platinum-based drugs. The overexpression of GSTs can lead to the rapid elimination of these drugs from the cells, reducing their efficacy and necessitating higher doses or alternative treatments.
Can GSTs Serve as Biomarkers for Cancer?
Yes, certain GST isoforms can serve as biomarkers for cancer diagnosis, prognosis, and treatment response. For example, the overexpression of GSTP1 is often used as a biomarker for predicting the response to chemotherapy and the likelihood of cancer recurrence. Monitoring GST levels can provide valuable insights into the aggressiveness of the cancer and the effectiveness of the treatment regimen.
Are GST Inhibitors a Viable Therapeutic Strategy?
Given their role in drug resistance, GST inhibitors are being explored as a therapeutic strategy to enhance the efficacy of chemotherapy. By inhibiting GST activity, these agents aim to prevent the detoxification of chemotherapeutic drugs, allowing them to remain active within the cancer cells for a longer period. Several GST inhibitors are currently under investigation in preclinical and clinical studies.
What is the Role of Genetic Polymorphisms in GSTs?
Genetic polymorphisms in GST genes can significantly affect an individual's susceptibility to cancer and their response to chemotherapy. Polymorphisms can lead to variations in enzyme activity, influencing the detoxification capacity of the cells. For example, the GSTM1 and GSTT1 null polymorphisms, where the genes are deleted, are associated with an increased risk of developing certain types of cancer due to reduced detoxification of carcinogens.
Future Directions in GST Research
Future research on GSTs in the context of cancer is likely to focus on several key areas. These include the development of more specific and potent GST inhibitors, the identification of new GST isoforms and their roles in cancer, and the exploration of GSTs as biomarkers for personalized cancer therapy. Additionally, understanding the interplay between GSTs and other cellular pathways involved in cancer progression and drug resistance will be crucial for developing comprehensive treatment strategies.
