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

Ehsanian R, Van Waes C, Feller SM - Cell Commun. Signal (2011)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USA. rezae@stanford.edu.

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.

No MeSH data available.


Related in: MedlinePlus

Cross talk between NF-κB and p53. There are many lines of crosstalk between the p53 and NF-κB pathways. A few of these are highlighted, such as AKT and the transcriptional co-activator proteins CREB-binding protein (CBP) and the related p300 protein. AKT can activate both IκB kinases (IKKs) and phosphorylate p65. AKT-mediated MDM2 phosphorylation can also inhibit p53 stabilization. Due to competition for the limited pool of CBP/p300, this protein also plays a crucial role in determining which pathway dominates in terms of cellular outcome. In addition, NF-κB has been shown to directly upregulate the levels of MDM2 mRNA and hence the protein. One promising aspect of quinacrine is its simultaneous ability to inhibit AKT, to induce the p53 pathway, and to inhibit the NF-κB pathway. Adapted from Dey et al. [279].
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Figure 3: Cross talk between NF-κB and p53. There are many lines of crosstalk between the p53 and NF-κB pathways. A few of these are highlighted, such as AKT and the transcriptional co-activator proteins CREB-binding protein (CBP) and the related p300 protein. AKT can activate both IκB kinases (IKKs) and phosphorylate p65. AKT-mediated MDM2 phosphorylation can also inhibit p53 stabilization. Due to competition for the limited pool of CBP/p300, this protein also plays a crucial role in determining which pathway dominates in terms of cellular outcome. In addition, NF-κB has been shown to directly upregulate the levels of MDM2 mRNA and hence the protein. One promising aspect of quinacrine is its simultaneous ability to inhibit AKT, to induce the p53 pathway, and to inhibit the NF-κB pathway. Adapted from Dey et al. [279].

Mentions: The deleterious roles of p53 inactivation [238,239] and nuclear factor-kB (NF-κB) hyperactivation [240,241] have been well established in human cancers. They lead to inhibition of cell death and promotion of oncogenesis. Cross talk between these two pathways has been identified and studied (Figure 3). It has been reported that p53 and NF-κB repress each other's activity by competing for transcriptional proteins such as p300 and CREB-binding protein (CBP) [242]. One signaling protein known to influence this competition is IKKα [243,244]. In particular, IKKα has been implicated in phosphorylating and directing CBP to participate in either the p53 or NF-κB pathway [243,244]. Another well studied signaling protein, AKT, can both activate IKKs as well as phosphorylate and enhance the transcriptional activity of p65 (NF-κB complex protein) [245-247]. In addition it has been demonstrated that AKT-mediated phosphorylation of MDM2 inhibits p53 stabilization [248]. Hence, it is likely that inhibitors of AKT activation could be utilized as anti-cancer agents for the inactivation of p53 and the inhibition NF-κB signaling.


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

Ehsanian R, Van Waes C, Feller SM - Cell Commun. Signal (2011)

Cross talk between NF-κB and p53. There are many lines of crosstalk between the p53 and NF-κB pathways. A few of these are highlighted, such as AKT and the transcriptional co-activator proteins CREB-binding protein (CBP) and the related p300 protein. AKT can activate both IκB kinases (IKKs) and phosphorylate p65. AKT-mediated MDM2 phosphorylation can also inhibit p53 stabilization. Due to competition for the limited pool of CBP/p300, this protein also plays a crucial role in determining which pathway dominates in terms of cellular outcome. In addition, NF-κB has been shown to directly upregulate the levels of MDM2 mRNA and hence the protein. One promising aspect of quinacrine is its simultaneous ability to inhibit AKT, to induce the p53 pathway, and to inhibit the NF-κB pathway. Adapted from Dey et al. [279].
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3117821&req=5

Figure 3: Cross talk between NF-κB and p53. There are many lines of crosstalk between the p53 and NF-κB pathways. A few of these are highlighted, such as AKT and the transcriptional co-activator proteins CREB-binding protein (CBP) and the related p300 protein. AKT can activate both IκB kinases (IKKs) and phosphorylate p65. AKT-mediated MDM2 phosphorylation can also inhibit p53 stabilization. Due to competition for the limited pool of CBP/p300, this protein also plays a crucial role in determining which pathway dominates in terms of cellular outcome. In addition, NF-κB has been shown to directly upregulate the levels of MDM2 mRNA and hence the protein. One promising aspect of quinacrine is its simultaneous ability to inhibit AKT, to induce the p53 pathway, and to inhibit the NF-κB pathway. Adapted from Dey et al. [279].
Mentions: The deleterious roles of p53 inactivation [238,239] and nuclear factor-kB (NF-κB) hyperactivation [240,241] have been well established in human cancers. They lead to inhibition of cell death and promotion of oncogenesis. Cross talk between these two pathways has been identified and studied (Figure 3). It has been reported that p53 and NF-κB repress each other's activity by competing for transcriptional proteins such as p300 and CREB-binding protein (CBP) [242]. One signaling protein known to influence this competition is IKKα [243,244]. In particular, IKKα has been implicated in phosphorylating and directing CBP to participate in either the p53 or NF-κB pathway [243,244]. Another well studied signaling protein, AKT, can both activate IKKs as well as phosphorylate and enhance the transcriptional activity of p65 (NF-κB complex protein) [245-247]. In addition it has been demonstrated that AKT-mediated phosphorylation of MDM2 inhibits p53 stabilization [248]. Hence, it is likely that inhibitors of AKT activation could be utilized as anti-cancer agents for the inactivation of p53 and the inhibition NF-κB signaling.

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USA. rezae@stanford.edu.

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.

No MeSH data available.


Related in: MedlinePlus