Dataset Information

Suppression of the Ubiquitin Pathway by Small Molecule Binding to Ubiquitin Enhances Doxorubicin Sensitivity of the Cancer Cells.

ABSTRACT: Development of inhibitors for ubiquitin pathway has been suggested as a promising strategy to treat several types of cancers, which has been showcased by recent success of a series of novel anticancer drugs based on inhibition of ubiquitin pathways. Although the druggability of enzymes in ubiquitin pathways has been demonstrated, ubiquitin itself, the main agent of the pathway, has not been targeted. Whereas conventional enzyme inhibitors are used to silence the ubiquitination or reverse it, they cannot disrupt the binding activity of ubiquitin. Herein, we report that the scaffolds of sulfonated aryl diazo compounds, particularly Congo red, could disrupt the binding activity of ubiquitin, resulting in the activity equivalent to inhibition of ubiquitination. NMR mapping assay demonstrated that the chemical directly binds to the recognition site for ubiquitin processing enzymes on the surface of ubiquitin, and thereby blocks the binding of ubiquitin to its cognate receptors. As a proof of concept for the druggability of the ubiquitin molecule, we demonstrated that Congo red acted as an intracellular inhibitor of ubiquitin recognition and binding, which led to inhibition of ubiquitination, and thereby, could be used as a sensitizer for conventional anticancer drugs, doxorubicin.

SUBMITTER: Nguyen T

PROVIDER: S-EPMC6471062 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Suppression of the Ubiquitin Pathway by Small Molecule Binding to Ubiquitin Enhances Doxorubicin Sensitivity of the Cancer Cells.

Nguyen Thanh T Ho Minh M Kim Kyungmin K Yun Sun-Il SI Mizar Pushpak P Easton James W JW Lee Seung Seo SS Kim Kyeong Kyu KK

Molecules (Basel, Switzerland) 20190319 6

Development of inhibitors for ubiquitin pathway has been suggested as a promising strategy to treat several types of cancers, which has been showcased by recent success of a series of novel anticancer drugs based on inhibition of ubiquitin pathways. Although the druggability of enzymes in ubiquitin pathways has been demonstrated, ubiquitin itself, the main agent of the pathway, has not been targeted. Whereas conventional enzyme inhibitors are used to silence the ubiquitination or reverse it, the ...[more]

PMID: 30893775

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Project description:BackgroundAnthracyclines are efficient and potent agents to treat broad range of cancers but cytotoxicity induced by them limits their use in therapeutics. Use of plant-derived agents help to prevent or delay the process of cancer progression and their combination increases the anti-cancer potential of mainstream compound. However, multidrug resistance is major cause of treatment failure in cancer patients.PurposeIn this study, combination treatments of fisetin or acacetin with doxorubicin were explored for their potential synergistic effect on non-small-cell lung carcinoma (NSCLC) cells.Study designDuring this study, NSCLC model cell lines A549 and H1299 were used to determine the combinatorial effect of phytochemicals namly acacetin and fisetin with doxorubicin.MethodsThe effects of individual compounds and their combination on cell viability, clonogenic potential and cell cycle progression were studied. Efflux of doxorubicin was measured by spectrofluorophotometer, whereas accumulation inside the cells was analyzed by flow cytometry and confocal microscopy. Expression of MDR1 was checked by semi-quantitative PCR.ResultsThe results showed that the cell viability of A549 and H1299 cells were significantly decreased in time- and dose-dependent manner, although A549 cells showed more sensitivity toward doxorubicin than H1299 cells. Mostly, combination of doxorubicin showed good synergy with acacetin in both the cell lines whereas, fisetin exerted synergistic effect only at 72 h of treatment in H1299 cells. Acacetin with doxorubicin caused G2/M arrest by downregulating CDK-cyclin complex in A549 cells. Acacetin-doxorubicin combination decreased the clonogenic potential of A549 and H1299 cells upto 82% and 59%, respectively, as compared to control. Acacetin also decreased efflux of doxorubicin by 59% after 30 mins of exposure to A549 cells and further increased accumulation of doxorubicin inside the cells upto 55% in 2 h. The modulatory effect of acacetin-doxorubicin combination on doxorubicin influx and efflux was mediated through downregulation of MDR1 treansporter in NSCLC cells.ConclusionThese findings suggested that acacetin augments the cytotoxicity of doxorubicin at lower concentrations in lung cancer cells. Their combination leads to more retention of doxorubicin in the cells by modulating drug trasporter and thus enhances its therapeutic potential.

Dataset Information

Suppression of the Ubiquitin Pathway by Small Molecule Binding to Ubiquitin Enhances Doxorubicin Sensitivity of the Cancer Cells.

Publications

Suppression of the Ubiquitin Pathway by Small Molecule Binding to Ubiquitin Enhances Doxorubicin Sensitivity of the Cancer Cells.

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