Repurposing drugs as pro‐oxidant redox modifiers to eliminate cancer stem cells and improve the treatment of advanced stage cancers

Abstract

Over the last decade, three major advances have contributed in improving the response rates against cancer including, immunotherapy; greater understanding of the molecular, biochemical, and cellular mechanisms in carcinogenesis thereby providing drug targets; and identification of reliable biomarkers for early detection to facilitate the earlier stage treatment of disease. However, no single universal cancer cure has yet been found, although combinations from the above areas have steadily improved survival outcomes. Hence, chemotherapy remains a key component in the oncologist's arsenal for cancer therapy, despite frequent development of drug resistance and more aggressive cancers with onset of advanced stage metastases. The focus here is to explore the repurposing of old drugs that cause pro‐oxidative overload to overcome onset of resistance to chemotherapy and enhance chemotherapeutic responses, particularly against metastatic cancer. Excellent examples of US Food and Drug Administration approved drugs suitable for repurposing are the potent and specific thioreductase inhibitor auranofin and the nonsteroidal anti‐inflammatory drug, celecoxib. Recently, both drugs were shown to selectively target and kill metastatic cancer cells and cancer stem cells (CSCs), predominantly by promoting excessive mitochondrial reactive oxygen species. Thus, targeting intracellular redox systems of advanced stage metastatic cancer cells and CSCs can promote an overload of pro‐oxidative stress to activate the intrinsic pathway for programmed cell death. It is envisaged that more clinical studies will incorporate longer term use of repurposed drugs, such as auranofin or celecoxib, to target redox systems in cancer cells as part of common practice postcancer diagnosis, providing enhanced chemotherapeutic responses and increased cancer survival.

Auranofin Enhances Sulforaphane-Mediated Apoptosis in Hepatocellular Carcinoma Hep3B Cells through Inactivation of the PI3K/Akt Signaling Pathway

“…Auranofin induces apoptosis of tumor cells and excessive reactive oxygen species (ROS) production by modulating the cellular redox status ( Marzano et al ., 2007 ; Cox et al ., 2008 ). Based on evidence that TrxR inhibition and ROS accumulation inhibited cancer cell growth, auranofin has been considered for an anti-cancer agent for leukemia, lung cancer and epithelial ovarian cancer ( Madeira et al ., 2012 ; Ralph et al ., 2019 ; U.S. National Library of Medicine, ClinicalTrials.gov ).…”

Auranofin Attenuates Non-Alcoholic Fatty Liver Disease by Suppressing Lipid Accumulation and NLRP3 Inflammasome-Mediated Hepatic Inflammation In Vivo and In Vitro

“…These compounds are suggested for their immunosuppressive activity by inhibiting immune cell activation [ 24 , 25 ]. Auranofin is a gold-containing compound and an FDA-approved drug for the treatment of rheumatoid arthritis and has been studied for potential preventive applications in several other diseases, including cancer, neurodegenerative disorders, pathogenic infections, and inflammation [ 26 , 27 , 28 ]. Auranofin can also inhibit phagocytosis by macrophages and can reduce proinflammatory cytokines through the inhibition of nuclear factor-kappa B activation [ 29 , 30 , 31 ].…”

PTEN, a Barrier for Proliferation and Metastasis of Gastric Cancer Cells: From Molecular Pathways to Targeting and Regulation

“…The involvement of the miR/PTEN axis in the drug resistance of GC cells can be attributed to their malignant behavior. To be more specific, when more cancer cells are at an advanced stage, the more they are resistant into chemotherapy [ 129 , 130 ]. Such a phenomenon can be associated with the miR/PTEN axis.…”