Discovery of Quinacrine as a Potent Topo II and Hsp90 Dual-Target Inhibitor, Repurposing for Cancer Therapy

Abstract

Topo II and Hsp90 are promising targets. In this study, we first verified the structural similarities between Topo IIα ATPase and Hsp90α N−ATPase. Subsequently, 720 compounds from the Food and Drug Administration (FDA) drug library and kinase library were screened using the malachite green phosphate combination with the Topo II-mediated DNA relaxation and MTT assays. Subsequently, the antimalarial drug quinacrine was found to be a potential dual−target inhibitor of Topo II and Hsp90. Mechanistic studies showed that quinacrine could specifically bind to the Topo IIα ATPase domain and inhibit the activity of Topo IIα ATPase without impacting DNA cleavage. Furthermore, our study revealed that quinacrine could bind Hsp90 N−ATPase and inhibit Hsp90 activity. Significantly, quinacrine has broad antiproliferation activity and remains sensitive to the multidrug−resistant cell line MCF−7/ADR and the atypical drug−resistant tumor cell line HL−60/MX2. Our study identified quinacrine as a potential dual−target inhibitor of Topo II and Hsp90, depending on the ATP−binding domain, positioning it as a hit compound for further structural modification.

Beyond Psychotropic: Repurposing of Fluoxetine Toward Cancer Management and Its Molecular Mechanisms

“…Metformin, the widely used antidiabetic drug, exhibited anticancer and chemosensitization properties in preclinical and clinical studies [16,17]. The antimalarial drug quinacrine was found to be a dual target antiproliferative agent by inhibition of Topo II and Hsp90 [18]. In addition, quinacrine was repurposed for managing cancer by other several mechanisms [19][20][21].…”

Beyond Psychotropic: Potential Repurposing of Fluoxetine toward Cancer Therapy

“…The antimalarial drug quinacrine was found to be a dual target antiproliferative agent via the inhibition of Topo II and Hsp90 [ 18 ]. In addition, quinacrine was repurposed for managing cancer by several other mechanisms [ 19 , 20 , 21 ].…”

“…Early observations showed conflicting findings on the antidepressants' effect on cancer promotion and growth [26,28]. Later studies revealed the great potential of antidepressant drugs, including tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), for repurposing to cancer The antimalarial drug quinacrine was found to be a dual target antiproliferative agent via the inhibition of Topo II and Hsp90 [18]. In addition, quinacrine was repurposed for managing cancer by several other mechanisms [19][20][21].…”

A Zymography technique to study amino acid activation by aminoacyl tRNA synthetases (aaRS): A broad spectrum, high-throughput tool to screen activities of aaRS and their “Urzyme” variants

“…phosphoserine phosphatase activity [17], library screenings for kinases [18] and, especially to measure primitive aminoacyl-tRNA synthetase (protozyme) activity [19]. We describe here the first adaptation of this assay into a simple, rapid, and sensitive zymography technique, with specific protocols, cognate amino acid-dependence, and insensitivity to phosphatase and kinase blockers, so that aaRS activities can be detected in both complex protein mixtures and purified samples.…”

“…In this new method, Malachite green and hexaammonium heptamolybdate tetrahydrate greatly enhance the intensity of the coloured complex with orthophosphates generated from PPi above and adjacent to active aaRS proteins in the gel[15]. The Malachite green assay was previously used by several groups to study cyclic nucleotide phosphodiesterase activity[16], phosphoserine phosphatase activity[17], library screenings for kinases[18] and, especially to measure primitive aminoacyl-tRNA synthetase (protozyme) activity[19]. We describe here the first adaptation of this assay into a simple, rapid, and sensitive zymography technique, with specific protocols, cognate amino acid-dependence, and insensitivity to phosphatase and kinase blockers, so that aaRS activities can be detected in both complex protein mixtures and purified samples.…”