Beyond DNA binding - a review of the potential mechanisms mediating quinacrine's therapeutic activities in parasitic infections, inflammation, and cancers

Abstract

This is an in-depth review of the history of quinacrine as well as its pharmacokinetic properties and established record of safety as an FDA-approved drug. The potential uses of quinacrine as an anti-cancer agent are discussed with particular attention to its actions on nuclear proteins, the arachidonic acid pathway, and multi-drug resistance, as well as its actions on signaling proteins in the cytoplasm. In particular, quinacrine's role on the NF-κB, p53, and AKT pathways are summarized.

Inhibition of spawning in zebrafish (Danio rerio): Adverse outcome pathways of quinacrine and ethinylestradiol

“…Though QUIN is a phospholipase A2 inhibitor, exposure had no effect on cPLA 2 expression levels. However, the mode of action of QUIN is to inhibit (Nagahama & Yamashita, 2008) the activity of cPLA 2 and does not seem to have an effect on transcription (Ehsanian et al, 2011). It was surprising that there was no effect seen on levels of PGF 2α, as a decrease in COX-2 suggests an interruption in the pathway responsible for the production of prostaglandins.…”

“…QUIN is a drug that disrupts the AA pathway by intercalating into the membrane phospholipids, inhibiting cPLA 2 binding and activity. The downstream effect of this interruption is decreased levels of leukotrienes, prostanoids and eicosanioid activity (Ehsanian, Van Waes, & Feller, 2011). QUIN has historically been used as a treatment for malaria, rheumatoid arthritis, and mild to moderate systemic lupus erythematosus and more recently, the neurodegenerative disease CreutzfeldtJakb disease (Vogtherr et al, 2003).…”

“…QUIN is a phospholipase A 2 inhibitor that was initially approved for use as an anti-malaria drug (Ehsanian et al, 2011). It has more recently been utilized in biological studies examining the ovulatory process in mammals and fish due to QUIN's ability to reduce the availability of AA pathway which is the substrate for the production of prostaglandins (Espey, Stein, & Dumitrescu, 1982;Berndtson & Goetz, 1986;).…”

The DNA Virus White Spot Syndrome Virus Uses an Internal Ribosome Entry Site for Translation of the Highly Expressed Nonstructural Protein ICP35

“…QC was originally developed as an antimalarial and antigiardiasis treatment (68,69), but it is now thought to have many other potential uses. Recently, QC was shown to induce an anticancer effect by simultaneously suppressing NF-B and activating p53 signaling (70)(71)(72), and it also acts against prions by inhibiting the formation of PrP Sc (73,74). QC also inhibits RNA recruitment and replication of the RNA genome of the Tomato bushy stunt virus (TBSV; a positive-sense RNA virus) in plants and in protoplasts (75).…”

Case Report and Literature Review: Quinacrine-induced Cholestatic Hepatitis in Undifferentiated Connective Tissue Disease

“…In terms of side effects, persistent abdominal cramping or diarrhea have been reported. Longterm, high-dose antimalarial therapy was occasionally reported to be associated with reversible hepatitis, presumably because of its tendency to concentrate in the liver 4 . Transient acute quinacrine hepatitis has been reported on 1 occasion in 1985 in a patient with UCTD; however, this was attributed to doses 3 times that of the recommended dose 5 .…”