A Chemical Genetic Screen for Modulators of Asymmetrical 2,2′-Dimeric Naphthoquinones Cytotoxicity in Yeast

Emadi, Ashkan; Ross, Ashley E.; Cowan, Kathleen M.; Fortenberry, Yolanda M.; Vuica‐Ross, Milena

doi:10.1371/journal.pone.0010846

Cited by 20 publications

(36 citation statements)

References 39 publications

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“…These results are similar to those obtained by Emadi et al [22], who evaluated the possible mechanism of action of bis-naphthoquinones and concluded that these compounds cause membrane depolarization.…”

Section: Discussionsupporting

confidence: 91%

Antifungal activity of synthetic naphthoquinones against dermatophytes and opportunistic fungi: preliminary mechanism-of-action tests

Ferreira

Cardoso

Silva

et al. 2014

Ann Clin Microbiol Antimicrob

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This study evaluated the antifungal activities of synthetic naphthoquinones against opportunistic and dermatophytic fungi and their preliminary mechanisms of action. The minimum inhibitory concentrations (MICs) of four synthetic naphthoquinones for 89 microorganisms, including opportunistic yeast agents, dermatophytes and opportunistic filamentous fungi, were determined. The compound that exhibited the best activity was assessed for its action against the cell wall (sorbitol test), for interference associated with ergosterol interaction, for osmotic balance (K+ efflux) and for membrane leakage of substances that absorb at the wavelength of 260 nm. All tested naphthoquinones exhibited antifungal activity, and compound IVS320 (3a,10b-dihydro-1H-cyclopenta [b] naphtho [2,3-d] furan-5,10-dione)-dione) demonstrated the lowest MICs across the tested species. The MIC of IVS320 was particularly low for dermatophytes (values ranging from 5–28 μg/mL) and Cryptococcus spp. (3–5 μg/mL). In preliminary mechanism-of-action tests, IVS320 did not alter the fungal cell wall but did cause problems in terms of cell membrane permeability (efflux of K+ and leakage of substances that absorb at 260 nm). This last effect was unrelated to ergosterol interactions with the membrane.

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Section: Discussionsupporting

confidence: 91%

Antifungal activity of synthetic naphthoquinones against dermatophytes and opportunistic fungi: preliminary mechanism-of-action tests

Ferreira

Cardoso

Silva

et al. 2014

Ann Clin Microbiol Antimicrob

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“…Mitochondrial electrochemical potential is correlated with the fluorescence intensity of Rho-123 (when decreased fluorescence means loss of the mitochondrial electrochemical potential) [42] . Flow cytometry was performed using a FACSCalibur (Becton Dickinson, San Jose, CA, USA) with excitation at 488 nm and emission read using a 525-to 550-nm filter (FL1).…”

Section: Assay Of the Electrochemical Potentialmentioning

confidence: 99%

Rosmarinic Acid Attenuates the Activation of Murine Microglial N9 Cells through the Downregulation of Inflammatory Cytokines and Cleaved Caspase-3

Coelho

Viau²,

Staub³

et al. 2017

Neuroimmunomodulation

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Objective: The present study evaluated the ability of rosmarinic acid (RA) to inhibit microglia activation induced by lipopolysaccharide (LPS) in the N9 murine microglial cell line, and investigated the putative mechanisms involved in this process. Methods: In all tests, N9 murine microglial cells were pretreated with RA (0.1, 1.0, and 10 μM) for 20 h and exposed to LPS (1 μM/mL) for 4 h. Cell viability was measured by Trypan blue exclusion assay. Flow cytometry was used to detect reactive oxygen species (ROS), quantify cleaved caspase-3, and analyze the mitochondrial electrochemical potential. iNOS, Arg-1, TNF-α, IL-1β, and IL-6 proteins were analyzed by Western blotting, and their antigens were detected using the chemiluminescence technique. The effect of RA on DNA was evaluated by the Comet assay. Results: RA attenuated the expression of the M1 marker iNOS and the levels of proinflammatory factors, including TNF-α, IL-1β, and IL-6; it increased the expression of the M2 marker Arg-1, and inhibited, at least in part, ROS generation and loss of mitochondrial outer membrane permeabilization through the inhibition of cleaved caspase-3 activation. RA also inhibited DNA damage, reassuring cell protection. Conclusions: The results suggested a protective effect of RA through downregulation of inflammatory cytokines and cleaved caspase-3.

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“…Mechanistic studies using a chemical genetic screen in yeast revealed that their cytotoxicity was probably related to their ability to undergo redox cycling, produce free radicals and cause mitochondrial dysfunction. 4 …”

Section: Introductionmentioning

confidence: 99%

Metabolic and electrochemical mechanisms of dimeric naphthoquinones cytotoxicity in breast cancer cells

Emadi

Harwood

et al. 2011

Bioorganic & Medicinal Chemistry

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Cancer cells reprogram their metabolism due to genetic alteration to compensate for increased energy demand and enhanced anabolism, cell proliferation, and protection from oxidative damage. Here, we assessed the cytotoxicity of three dimeric naphthoquinones against the glycolytic MCF-7 versus the oxidative MDA-453 breast carcinoma cell lines. Dimeric naphthoquinones 1 and 2 impaired MDA-453, but not MCF-7, cell growth at IC50 = 15 μM. Significant increase in reactive oxygen species, decrease in oxygen consumption and ATP production were observed in MDA-453 cells but not in MCF-7 cell. These findings suggest that oxidative stress and mitochondrial dysfunction are mechanisms by which these agents exert their cytotoxic effects. Cyclic voltammetry and semi-empirical molecular orbital calculations further characterized the electrochemical behavior of these compounds. These results also suggest that dimeric naphthoquinones may be used to selectively target cancer cells that depend on oxidative phosphorylation for energy production and macromolecular synthesis.

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A Chemical Genetic Screen for Modulators of Asymmetrical 2,2′-Dimeric Naphthoquinones Cytotoxicity in Yeast

Cited by 20 publications

References 39 publications

Antifungal activity of synthetic naphthoquinones against dermatophytes and opportunistic fungi: preliminary mechanism-of-action tests

Antifungal activity of synthetic naphthoquinones against dermatophytes and opportunistic fungi: preliminary mechanism-of-action tests

Rosmarinic Acid Attenuates the Activation of Murine Microglial N9 Cells through the Downregulation of Inflammatory Cytokines and Cleaved Caspase-3

Metabolic and electrochemical mechanisms of dimeric naphthoquinones cytotoxicity in breast cancer cells

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