Quinacrine inhibits GSTA1 activity and induces apoptosis through G1/S arrest and generation of ROS in human non-small cell lung cancer cell lines

Kumar, M. Sriram; Martin, Ansie; Nirgude, Snehal; Chaudhary, Bibha; Mondal, Sukanta; Sarkar, Angshuman

doi:10.18632/oncotarget.27558

Cited by 12 publications

(16 citation statements)

References 45 publications

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“…Apart from phospholipase A 2 , other molecular targets of QC that could have a potential impact on tumorigenicity have not been covered as well. Recently we worked on this aspect and discovered a novel interaction of QC with GSTA1 which encodes the GSTα protein and is well known for its prominent role in cancer cell proliferation, survival, and most importantly chemoresistance [19]. Here, we report a novel interaction of quinacrine with FGFR receptor family member FGFR1 and inhibition of its kinase activity and downstream cellular processes by QC.…”

Section: Introduction:-mentioning

confidence: 85%

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Quinacrine binds to the kinase domain of FGFR1 and inhibits its activity

Kumar

Sarkar

2021

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BackgroundFGF family receptors, especially FGFR1, have been widely implicated for their potential role in the promotion of oncogenesis and chemoresistance in lung cancer. Quinacrine, an anti-malarial drug, has been widely reported to exhibit anti-neoplastic properties through the activation of p53 and simultaneous inhibition of NF-kB signaling pathways in cancer cells.MethodsThe binding of QC to FGFR1 was studied using molecular docking and molecular dynamics simulation studies. The experimental kinase activity assay for the protein was performed using a luminescence-based kinase assay. FGF-induced phosphorylation and proliferation were studied by cell counting and western blotting. Matrigel-based cell migration was conducted to assess migration activity.ResultsQC interacted with multiple residues around the kinase insert domain of FGFR1 through hydrogen bonding, hydrophobic interactions, and water bridges. The kinase activity inhibition assay demonstrated a significant reduction in FGFR1 kinase activity by QC at higher concentrations, which was further observed at the cellular level in inhibition of FGFR1 phosphorylation and proliferation by QC at higher exposure concentrations of FGF stimulated cells. These effects were further validated downstream in the FGF-induced activation of cell migration.ConclusionQC did form a stable interaction with residues of FGFR1 at another allosteric site surrounding the kinase domain, leading to inhibition of its kinase activity at higher drug concentrations. This effect was further observed at the cellular level in both acidic and basic FGF ligand-induced proliferation, phosphorylation of FGFR1, and cell migration, where a trend of significant reduction in activity was observed at higher drug concentrations.

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Section: Introduction:-mentioning

confidence: 85%

“…Quantification was performed using the Bradford method, and approximately 40µg of cell lysate was run and normalized on a 10 %-12% SDS-PAGE gel. The resolved gel was then transferred to a polyvinylidene fluoride membrane and processed as previously reported [19].…”

Section: Rna Isolation and Reverse Transcriptase-pcr Analysismentioning

confidence: 99%

Quinacrine binds to the kinase domain of FGFR1 and inhibits its activity

Kumar

Sarkar

2021

Preprint

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“…A total of 75,000 cells/mL of MCF7 and MDA-MB-231 were seeded in 6-well plates and treated with different doses of ST09 (0, 20, 40, 80, 100, and 120 nM) for 24 and 48 h. Cells were then trypsinized using TrpLE TM Express Enzyme (1X, Gibco TM ), washed twice by cold 1X PBS, and fixed in 80% cold ethanol overnight at −20 ° C as described [ 14 ]. Post fixation, cells were again washed twice with cold PBS followed by RNase A treatment (1 mg/mL RNase in 1X PBS) for 30 min at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

ST09, A Novel Curcumin Derivative, Blocks Cell Migration by Inhibiting Matrix Metalloproteases in Breast Cancer Cells and Inhibits Tumor Progression in EAC Mouse Tumor Models

et al. 2020

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Purpose: Curcumin is known for its anticancer and migrastatic activity in various cancers, including breast cancer. Newer curcumin derivatives are being explored to overcome limitations of curcumin like low bioavailability, stability, and side effects due to its higher dose. In this study, the synthesis of ST09, a novel curcumin derivative, and its antiproliferative, cytotoxic, and migrastatic properties have been explored both in vitro and in vivo. Methods: After ST09 synthesis, anticancer activity was studied by performing standard cytotoxicity assays namely, lactate dehydrogenase (LDH) release assay, 3-(4, 5-dimethylthiazol-2-yl)-2–5-diphenyletrazolium bromide (MTT), and trypan blue exclusion assay. Annexin-FITC, cell cycle analysis using flow cytometry, and Western blotting were performed to elucidate cell death mechanisms. The effect on the inhibition of cell migration was studied by transwell migration assay. An EAC (Ehrlich Ascites carcinoma) induced mouse tumor model was used to study the effect of ST09 on tumor regression. Drug toxicity was measured using aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), and flow-cytometry based lymphocyte count. Histological analysis was performed for assessment of any tissue injury post ST09 treatment. Results: ST09 shows an approximate 100-fold higher potency than curcumin, its parent compound, on breast tumor cell lines MCF-7 and MDA-MB231. ST09 arrests the cell cycle in a cell type-specific manner and induces an intrinsic apoptotic pathway both in vitro and in vivo. ST09 inhibits migration by downregulating matrix metalloprotease 1,2 (MMP1,2) and Vimentin. In vivo, ST09 administration led to decreased tumor volume in a mouse allograft model by boosting immunity with no significant drug toxicity. Conclusion: ST09 exhibits antiproliferative and cytotoxic activity at nanomolar concentrations. It induces cell death by activation of the intrinsic pathway of apoptosis both in vitro and in vivo. It also inhibits migration and invasion. This study provides evidence that ST09 can potentially be developed as a novel antitumor drug candidate for highly metastatic and aggressive breast cancer.

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“…Among the electrophilic compounds that are detoxified by hGSTA1-1 are several alkylating chemotherapeutics that are used in the treatment of cancer (e.g., busulfan, chlorambucil, etc.) [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. This phenomenon, in combination with the overexpression of GSTs in cancer cells, is associated with developing resistance to many anticancer drugs [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…To this end, one of the strategies being developed to address this problem relies on applying GST-targeted inhibitors. Numerous compounds with different degrees of efficacy and inhibition potency have already been studied over the last years [ 7 , 11 , 12 , 13 , 14 , 15 , 20 , 21 , 22 , 23 , 24 ]. GST inhibitors are classified according to their binding specificity [ 1 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

The Interaction of Human Glutathione Transferase GSTA1-1 with Reactive Dyes

et al. 2021

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Human glutathione transferase A1-1 (hGSTA1-1) contributes to developing resistance to anticancer drugs and, therefore, is promising in terms of drug-design targets for coping with this phenomenon. In the present study, the interaction of anthraquinone and diazo dichlorotriazine dyes (DCTD) with hGSTA1-1 was investigated. The anthraquinone dye Procion blue MX-R (PBMX-R) appeared to interact with higher affinity and was selected for further study. The enzyme was specifically and irreversibly inactivated by PBMX-R, following a biphasic pseudo-first-order saturation kinetics, with approximately 1 mol of inhibitor per mol of the dimeric enzyme being incorporated. Molecular modeling and protein chemistry data suggested that the modified residue is the Cys112, which is located at the entrance of the solvent channel at the subunits interface. The results suggest that negative cooperativity exists upon PBMX-R binding, indicating a structural communication between the two subunits. Kinetic inhibition analysis showed that the dye is a competitive inhibitor towards glutathione (GSH) and mixed-type inhibitor towards 1-chloro-2,4-dinitrobenzene (CDNB). The present study results suggest that PBMX-R is a useful probe suitable for assessing by kinetic means the drugability of the enzyme in future drug-design efforts.

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Quinacrine inhibits GSTA1 activity and induces apoptosis through G1/S arrest and generation of ROS in human non-small cell lung cancer cell lines

Cited by 12 publications

References 45 publications

Quinacrine binds to the kinase domain of FGFR1 and inhibits its activity

Quinacrine binds to the kinase domain of FGFR1 and inhibits its activity

ST09, A Novel Curcumin Derivative, Blocks Cell Migration by Inhibiting Matrix Metalloproteases in Breast Cancer Cells and Inhibits Tumor Progression in EAC Mouse Tumor Models

The Interaction of Human Glutathione Transferase GSTA1-1 with Reactive Dyes

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