Superoxide dismutase and the sigma1 receptor as key elements of the antioxidant system in human gastrointestinal tract cancers

This long-term research was designed to evaluate whether superoxide dismutase (SOD) isoenzymes participate in the development of human gastrointestinal neoplasms and the potential influence of the sigma1 receptor (Sig1R) on the regulation of SOD gene expression during the neoplastic process. The experiments included human tissues from selected gastrointestinal tract tumors (liver cancer, colorectal adenocarcinoma, and colorectal cancer liver metastases). Activity, protein levels, and mRNA levels were determined for SOD isoenzymes and Sig1R. Additionally, markers of oxidative stress (glutathione, lipid peroxidation) were measured. The results showed significant changes in the antioxidant system activity in all examined types of tumors. SOD changed both in healthy cells and in neoplastic cells. The activity and expression of all studied enzymes significantly changed due to the advancement of tumor development. The Sig1R might be an additional regulator of the antioxidant system on which activity might depend on the survival and proliferation of cancer cells. Overall, the study shows that SOD1 and SOD2 are involved not only in the formation of neoplastic changes in the human gastrointestinal tissues (healthy intestine – colon tumor; healthy liver – liver cirrhosis – liver cancer) but also in the development of tumors in the sequence: benign tumor – malignant tumor – metastasis.

Dual Aquaporin and Sigma1 Receptor (DAS) Modulators: New Tools for Counteracting Oxidative Stress

Specific aquaporins (AQP), called peroxyporins, play a relevant role in controlling H2O2 permeability and ensure reactive oxygen species wasting during oxidative stress. Another target involved in oxidative stress is the Sigma1 Receptor (S1R), since its activation is triggered by oxidative or endoplasmic reticulum stress. Herein we evaluated the effect of S1R modulators on AQP-dependent water permeability in the presence and in the absence of oxidative stress. Applying stopped-flow light scattering and fluorescent probe methods, water and hydrogen peroxide permeability in Hela cells have been studied. Results evidenced that S1R agonists can restore water permeability in heat-stressed cells and the co-administration with a S1R antagonist totally counteracted the ability to restore the water permeability. All compounds except one were able to counteract the oxidative stress of HeLa cells specifically knocked down for S1R. Taken together, our results support the hypothesis that the investigated compounds act as dual aquaporin and Sigma1 receptor (DAS) modulators. The finding that small molecules can modulate both AQP and S1R opens a new direction toward the identification of innovative drugs able to regulate cell survival during oxidative stress in pathologic conditions, like cancer and degenerative diseases.

Novel Dual Ligands Targeting Sigma1 Receptor and Acetylcholinesterase Endowed with Antioxidant Properties

Neurodegenerative disorders represent one of the main therapeutic challenges of our time. [...]