The unique mechanism of p53 upregulation which differs from the genotoxic upregulation of p53 was not investigated by Wang et al. , but Gurova et al. , found the induction of p53 to be linked to the inhibition of NF-κB. These results were later extended using a skin inflammation mouse model where the contact hypersensitivity (CHS) response to chemical allergen sensitization was evaluated . In this mouse model the authors identified NF-κB to be critical in the development of the contact hypersensitivity response and demonstrated that quinacrine reduced CHS by inhibiting NF-κB activation and as well as cytokines (TNFα, IL-1β, and CCL21) that are dependent on NF-κB activation .
NF-κB is also a key regulator of cytokine-induced expression of endothelial cellular adhesion molecules (CAMs) [254, 255]. The inhibitory effect of quinacrine on NF-κB in this context was supported in experiments where NiCl2- and CoCl2-induced cellular activation of ICAM-1 was inhibited by quinacrine . The effect was attributed to PLA2 because the enzyme causes the generation of platelet activation factor and eicosanoids , which are thought to play a role in the activation of NF-κB .
NF-κB has been recently shown to also depend on arachidonic acid metabolites  and upstream inhibition by quinacrine has been proposed to inhibit the activation of NF-κB due to its inhibitory effects on PLA2 . In a study evaluating the effect of lysophosphatidic acid (LPA) on endothelial cell activation, quinacrine blocked LPA-stimulated activation of NF-κB as well as the increase in expression of genes known to be dependent on the activation of the NF-κB transcription factor: E-selectin, ICAM-1, IL-8, and MCP-1 .
Another interesting line of investigation further revealed that reactive oxygen intermediates (ROI) are implicated in UVB-induced expression of TNFα in keratinocytes and that COX products and, more importantly, LOX products, also known as eicosanoids, which are themselves products of an oxidative metabolism, are the main ROI implicated in this induction . The investigators hypothesize that eicosanoids likely exert their function through activation of NF-κB . They also attributed the reduction of TNFα mRNA after quinacrine administration to the inhibitory activity of quinacrine on PLA2, based on reports showing that UVB can induce PLA2 in keratinocytes [262–264]. Another study investigating the source of oxygen radicals which activate Kupffer cell NF-κB after co-culture with AH70 cells attributed the attenuation of oxidative NF-κB activation to the PLA2 inhibitory activity of quinacrine .
However, because many studies do not directly implicate PLA2 inhibition by quinacrine as the mechanism of NF-κB inhibition and in light of more recent investigations challenging the notion that quinacrine acts primarily as an inhibitor of PLA2 [200, 253, 266], quinacrine's effect is presumably, at least partially, due to NF-κB inactivation via a mechanism other than PLA2 inhibition. Pupe et al.  present another intriguing mechanism for NF-κB inactivation as their experiments revealed quinacrine to inhibit UVB-induced IκBα degradation. However, this type of inhibition may be tumor-specific since another mechanism of NF-κB inhibition, nuclear translocation and sequestration of an inactive complex, has been well documented.
Unlike other NF-κB inhibitors, quinacrine does not inhibit the NF-κB pathway via cytoplasmic sequestration of p65. Instead, published experiments indicate a mechanism involving confinement of the p65 complex in the nucleus in an inactive state . The increased presence of NF-κB in the nucleus after quinacrine exposure was supported by experiments revealing increased DNA binding of NF-κB after quinacrine treatment alone or in combination with TNFα . These experiments also revealed that quinacrine plus TNFα induced greater NF-κB DNA binding than TNFα treatment alone. The lack of DNA binding inhibition of NF-κB after quinacrine treatment was also confirmed in a report by Fabbri et al. .
Down-regulation of p65 Ser536 phosphorylation by IKKα has been suggested as the primary mechanism of action for quinacrine . The physiological importance of this inhibition was recently confirmed in the skin inflammation mouse model described in a previous section . Further support of this mechanism was attained by Na et al. when hydrogen peroxide-induced phosphorylation of the p65 subunit of NF-κB was partially inhibited by quinacrine . The effects of quinacrine on NF-κB are in line with its uses in the treatment of inflammatory diseases as a single agent or in combination with other medications . As discussed further below, first hints of the mechanism by which quinacrine may inhibit the NF-κB pathway and promote the p53 pathway have come from studies with 9-aminoacridine (9AA), which implicated AKT and mTOR as targets for quinacrine .