Many GSK-3β inhibitors (GSKi) have been identified. They are known to induce apoptosis in leukemia and pancreatic cancer cells, and can destabilize p53, which may promote cellular death in response to DNA damaging agents (Wang et al, 2008; Beurel et al, 2009). Administration of GSKi inhibited cochlear destruction in cisplatin-injected mice (Park et al, 2009).
Lithium is a selective ATP competitive inhibitor of GSK-3 (Ryves and Harwood, 2001). Lithium carbonate used with bipolar disorder patients (Moore et al, 2009). LY2090314 has been in clinical trials for metastatic pancreatic cancer and acute leukemia ([NCT01632306], [NCT01287520], [NCT01214603]). Clinical trials of GSKi for Alzheimer's disease were unsuccessful.
The use of GSKi remains controversial because of their possibly oncogenic properties. Evaluation of GSKi in clinical trials has been hampered by the fear that inhibition of GSK-3 may stimulate or aid in malignant transformation as GSK-3 can phosphorylate pro-oncogenic factors such as beta-catenin, c-Jun and c-Myc which targets them for degradation (Patel & Woodgett, 2008). However, no studies have been reported suggesting that treatment of mice with GSKi resulted in an increase in cancer incidence. In fact, many patients with bipolar disorder have been treated with lithium for prolonged periods of time, with no evidence that these patients have increased incidences of cancer (McCubrey et al, 2014).
The GSKi kenpaullone and lithium chloride were found to reduce viral Nucleoprotein phosphorylation in the severe acute respiratory syndrome CoV-infected VeroE6 cells and decrease the viral titer and cytopathic symptoms. Effects of GSK-3 inhibition were reproduced in another coronavirus, the neurotropic JHM strain of mouse hepatitis virus (Wu et al, 2009).