Thioredoxin reductase (TrxR) plays a central role within the antioxidant system and reacts with reactive oxygen species (ROS) to overcome oxidative stress. Many cancers overexpress TrxR; such overexpression is shown to be essential for maintaining tumor phenotypes and metastasis. As such, inhibition of TrxR has been a long-standing concept behind development of novel cancer therapeutics. Previous efforts to effectively kill cancer cells by targeting TrxR have been unsuccessful. Small molecule inhibitors targeting TrxR have shown non-significant changes in cell proliferation, and inhibition by TrxR knockdown has no significant effect. This is likely due to the robust and multinodal antioxidant system present in cancer cells. With this challenge in mind, a combinatorial approach to target TrxR and redox cycling may be necessary to overcome the inherent redundancy in the antioxidant system and terminally disrupt cancer cell homeostasis.
Dr. Arambula and Dr. Sessler have combined the properties of gold(1) N-heterocylic carbenes (NHC) complexes, which can inhibit TrxR, with quinones, which are known redox cycling agents that can lead to ROS overproduction, to rationally design a novel class of compounds (i.e., complex 1) that can both inhibit TrxR and redox cycling. Complex 1 is a quinone bearing Au-NHC carbene and is thought to perturb antioxidant homeostasis with duel assault by inhibiting TrxR-based ROS mediation as well as increasing ROS production. This two-pronged approach overwhelms the antioxidant network and promotes cell death in cancer cells. Cellular studies in multiple human cancer cell lines have shown that complex 1 induces cell death, significantly inhibits TrxR and accentuates ROS, and outperforms current in clinic oxidative stressors like Doxorubicin. In zebrafish embryos bearing human lung cancer xenografts, complex 1-induced cancer specific cell death while demonstrating minimal toxicity to normal host cells. Ongoing and unpublished results also suggest that these compounds are able to trigger enhanced biomarker display on cancer cells which induces Immunogenic Cell Death (ICD). Compounds with ICD inducing capabilities are excellent candidates for complementing immunotherapies.
We have filed a PCT application for this technology and are seeking an industry partner to help bring this technology to the clinic.
Figure 1. Complex 1 induces cancer cell specific cell death in zebrafish tumor xenografts. Panels A-H are a lateral view of 3-day-old zebrafish tumor xenografts treated with either DMSO or Complex 1. Red fluorescence (DiI) shows lung cancer cells in A and E, whereas apoptotic cells are shown by green fluorescence (acridine orange.) DMSO-treated xenografts show very few dead cells, but Complex 1 treated cells display cell death in a majority of tumor cells.