Repurposing Thioridazine (TDZ) as an anti-inflammatory agent

Abstract

Nuclear factor-kB (NF-kB) is a crucial transcription factor in the signal transduction cascade of the inflammatory signaling. Activation of NF-κB depends on the phosphorylation of IκBα by IκB kinase (IKKβ) followed by subsequent ubiquitination and degradation. This leads to the nuclear translocation of the p50- p65 subunits of NF-κB, and further triggers pro-inflammatory cytokine gene expression. Thus, in the need of a more effective therapy for the treatment of inflammatory diseases, specific inhibition of IKKβ represents a rational alternative strategy to the current therapies. A computer-aided drug identification protocol was followed to identify novel IKKβ inhibitors from a database of over 1500 Food and Drug Administration (FDA) drugs. The best scoring compounds were compared with the already known high-potency IKKβ inhibitors for their ability to bind and inhibit IKKβ by evaluating their docking energy. Finally, Thioridazinehydrochloride (TDZ), a potent antipsychotic drug against Schizophrenia was selected and its efficiency in inhibiting IκBα protein degradation and NF-κB activation was experimentally validated. Our study has demonstrated that TDZ blocks IκBα protein degradation and subsequent NF-κB activation to inhibit inflammation. Thus, it is a potential repurposed drug against inflammation.

Inhibition of Fatty Acid Oxidation as a New Target To Treat Primary Amoebic Meningoencephalitis

“…Later, TDZ was also shown to be a selective inhibitor of peroxisomal β-oxidation ( 25 , 26 ). It is now being repurposed as an anticancer, anti-inflammatory, and antimicrobial agent ( 35 – 38 ). The pharmacokinetics of TDZ are well studied.…”

Artificial intelligence, machine learning, and drug repurposing in cancer

“…Regardless of these limitations, there are several examples of successful dockingbased drug off-target activity predictions [99]. For instance, antipsychotic agent thioridazine was found among 1500 FDAapproved compounds to possess anti-inflammatory activity by binding and inhibiting IκB kinase, which is critical for the NF-ΚB pathway [100]. Similarly, virtual docking accurately predicted inhibitory activity of five compounds from a collection of more than 1400 FDA-approved drugs against Pseudomonas aeruginosa quorum-sensing (population-wide virulence) mechanisms, with antipsychotic agent pimozide displaying potent in vitro activity in inhibiting bacterial virulence gene expression [101].…”

Theeffect of Doxorubicin and Thioridazine on Squamous Carcinoma Cell Line

“…On the other hand, the least viability that was noted in the combination group VI, could be attributed to the growth inhibitory effects of TZ which include anti-proliferative and anti-apoptotic properties such as the down regulation of cyclin D1 and cyclin dependent kinase 4 (CDK4), which are associated with the transition from G1 to S phase, the up -regulation of the CDK inhibitors p16 and p27, which interrupts cell cycle procession at the G1 or G2/M phase. Also, it up-regulates antiapoptotic markers such as Bax and p53 [22][23][24][25][26] .…”