National University of Singapore, Singapore
Assoc. Prof. Dr. Chew Eng Hui received her B.Sc.Pharmacy with Honours degree from the National University of Singapore (NUS), Singapore. Upon completing her doctorate in drug discovery at the University of Nottingham, UK, she joined Professor Arne Holmgren’s lab as a postdoctoral fellow at Karolinska Institute, Sweden to further her studies in redox signaling. In 2008, she joined NUS as Assistant Professor at the Department of Pharmacy and was appointed Associate Professor in 2015.
Assoc. Prof. Dr. Chew’s research interests are focused on understanding the involvement of redox signaling in malignant transformation and to employ this knowledge for the identification and development of rational therapeutic strategies. For this, her particular interest has been focused on exploring the potential of developing naturally occurring or semi-synthetic electrophilic compounds into chemotherapeutics, cytoprotective, neuroprotective and/or anti-inflammatory agents through their redox modulating activities.
The Thioredoxin System – A Friend or Foe in Disease States and Its Relevance as a Target in Anticancer Treatment
The thioredoxin and glutathione systems are the two major thiol redox systems that maintains intracellular redox homeostasis. The thioredoxin (Trx) system comprises Trx, thioredoxin reductase (TrxR) and NADPH. TrxR catalyzes the NADPH-dependent reduction of the active site disulfide of oxidized Trx. To protect cellular proteins from oxidative damage, Trxs use a conserved redox active dithiol/disulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide exchange reactions. Emerging findings have indicated that the dysregulated levels of the components of the Trx system has led to different disease states. Our laboratory has taken the interest to investigate the Trx system’s involvement in regulating apoptosis and it has been found that thioredoxin-1 (Trx-1) is capable of regulating DNA damage mediated by apoptosis inducing factor (AIF). The identification of the interaction between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or prevent this protein-protein interaction for treatment of different disease states. While Trx is required for regulation of cell proliferation and apoptosis, on the other hand, in cancer, the biological effects of the Trx system contribute to tumor growth and progression. In the light of the high prevalence of cancer and refractoriness of malignant tumors to clinical agents, novel molecular targets need to be identified and new chemotherapeutics be discovered. Accumulating evidence has indicated that the selenocysteine-dependent TrxR enzyme is a valid molecular target for anticancer drug development. Numerous natural products and synthetic compounds, including several clinically used chemotherapeutics have been recognized to target TrxR. A number of structurally diversified compounds derived from natural sources have also been found to possess potent inhibitory effect against TrxR. In our laboratory, we had evaluated the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their derivatives on TrxR activity. Sharing in common electrophilic centers, these compounds had been found to possess TrxR inhibitory activity correlating to their antiproliferative activity. On this basis, these compounds can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical outcomes.