Fluconazole induces ROS in Cryptococcus neoformans and contributes to DNA damage in vitro

Peng, Congyue Annie; Gaertner, Andrea A.E.; Henriquez, Sarah Ana; Fang, Diana; Colón-Reyes, Rodney J.; Brumaghim, Julia L.; Kozubowski, Lukasz

doi:10.1371/journal.pone.0208471

Cited by 32 publications

(32 citation statements)

References 69 publications

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“…32 In addition, copper ions bind strongly to DNA and disrupt the doublestranded structure 33 , thus adversely affecting drug binding to DNA. The findings of our research were not consistent with the findings of Peng and her coworkers 34 who stated that fluconazole contributed to an increase of the DNA damage in vitro when complexed with iron or copper in the presence of hydrogen peroxide. In our opinion, the inconsistency was because they treated 0.1 pmol pBSSK plasmid DNA equal to 296400 µM bp of the plasmid with 50 µM of fluconazole.…”

Section: Discussioncontrasting

confidence: 99%

In vitro and in silico analysis of the effect of fluconazole, an antifungal drug, on DNA

Zarf

Arman

2020

JSCS

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It must be stressed that the manuscript still has to be subjected to copyediting, typesetting, English grammar and syntax corrections, professional editing and authors' review of the galley proof before it is published in its final form. Please note that during these publishing processes, many errors may emerge which could affect the final content of the manuscript and all legal disclaimers applied according to the policies of the Journal.

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Section: Discussioncontrasting

confidence: 99%

In vitro and in silico analysis of the effect of fluconazole, an antifungal drug, on DNA

Zarf

Arman

2020

JSCS

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“…While diminishment of ergosterol is a well-documented cause of FLC-mediated growth inhibition of C. neoformans , additional possible effects of FLC on C. neoformans cells have been proposed. FLC treatment has been shown to cause an increase in reactive oxygen species (ROS) in Candida albicans [16–18] and most recently in C. neoformans [19]. ROS are molecules with unpaired, highly reactive electrons called free radicals, generated during basic cellular processes, or due to external stress-inducing conditions, including environmental pollutants, foreign compounds such as drugs or chemicals, and exposure to X-rays [20].…”

Section: Introductionmentioning

confidence: 99%

“…FLC-mediated increase in ROS could contribute towards oxidative stress in C. neoformans. Consistent with FLC-triggered ROS contributing to growth inhibition, co-treatment of C. neoformans cells with FLC and the antioxidant ascorbic acid (AA) was shown to partially rescue C. neoformans cells from FLC-mediated growth inhibition [19]. Similarly, co-treatment of C. albicans cells with the anti-fungal drug miconazole and a synthetic antioxidant, pyrrolidine dithiocarbamate (PDTC), has been shown to increase the Minimal Inhibitory Concentration (MIC) of miconazole [18].…”

Section: Introductionmentioning

confidence: 99%

“…To counteract harmful effects of copper, C. neoformans increases expression of metallothionein genes, CMT1 and CMT2 , which bind to and sequester copper [29]. Previous studies have shown that C. neoformans mutants lacking metallothionein genes exhibit attenuated virulence [30] and show an increased sensitivity to FLC [19]. These findings suggest that Cmt1 and Cmt2 proteins allow for reversal of some of the harmful effects of ROS generated in the presence of FLC.…”

Section: Introductionmentioning

confidence: 99%

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Increase of reactive oxygen species contributes to growth inhibition by fluconazole in Cryptococcus neoformans

et al. 2019

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Background: Cryptococcus neoformans, a basidiomycetous yeast, is a fungal pathogen that can colonize the lungs of humans causing pneumonia and fungal meningitis in severely immunocompromised individuals. Recent studies have implied that the antifungal drug fluconazole (FLC) can induce oxidative stress in C. neoformans by increasing the production of reactive oxygen species (ROS), as presence of the antioxidant ascorbic acid (AA) could reverse the inhibitory effects of FLC on C. neoformans. However, in Candida albicans, AA has been shown to stimulate the expression of genes essential for ergosterol biosynthesis. Hence, the contribution of ROS in FLC-mediated growth inhibition remains unclear. Results: In order to determine whether counteracting ROS generated by FLC in C. neoformans can contribute to diminishing inhibitory effects of FLC, we tested three other antioxidants in addition to AA, namely, pyrrolidine dithiocarbamate (PDTC), retinoic acid (RA), and glutathione (GSH). Our data confirm that there is an increase in ROS in the presence of FLC in C. neoformans. Importantly, all four antioxidants reversed FLC-mediated growth inhibition of C. neoformans to various extents. We further verified the involvement of increased ROS in FLC-mediated growth inhibition by determining that ROS-scavenging proteins, metallothioneins (CMT1 and CMT2), contribute to growth recovery by PDTC and AA during treatment with FLC. Conclusion: Our study suggests that ROS contributes to FLC-mediated growth inhibition and points to a complex nature of antioxidant-mediated growth rescue in the presence of FLC.

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“…Following mitochondrial dysfunction, elevated levels of ROS will contribute to tumorigenesis signaling pathways. Increased ROS may also damage the DNA,7 proteins, and lipids, and ultimately lead to the development of cancer.…”

Section: Introductionmentioning

confidence: 99%

<p>In vitro mitochondrial-targeted antioxidant peptide induces apoptosis in cancer cells</p>

Zhan¹,

Liao²,

Li³

et al. 2019

OTT

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IntroductionReactive oxygen species (ROS) are major contributors to cancer and involved in numerous tumor proliferation signaling pathways. Mitochondria are the major ROS-producing organelles, and ROS are produced from the synthesis of adenosine triphosphate and cell metabolism.MethodsA novel mitochondria-targeted peptide, namely KRSH, was synthesized and characterized. KRSH consists of four amino acids; lysine and arginine contain positively charged groups that help KRSH target the mitochondria, while tyrosine and cysteine neutralize excessive endogenous ROS, thereby inhibiting tumorigenesis.ResultsThe results indicated that KRSH is specifically inhibiting the growth of HeLa and MCF-7 cancer cell lines. However, MCF10A cells can resist the effects of KRSH even in a relative higher concentration. The dichloro-dihydro-fluorescein diacetate and MitoSOXTM Red assay suggested that KRSH drastically decreased the level of ROS in cancer cells. The mitochondrial depolarization assay indicated that treatment with KRSH at a dose of 50 nM may decrease the mitochondrial membrane potential leading to apoptosis of HeLa and MCF-7 cells.ConclusionIn other studies, investigating rat liver mitochondria, the uptake of KRSH may reach 80% compared with that for mitoquinone. Therefore, KRSH was designed as a superior peptide antioxidant and a mitochondria-targeting anticancer agent.

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Fluconazole induces ROS in Cryptococcus neoformans and contributes to DNA damage in vitro

Cited by 32 publications

References 69 publications

In vitro and in silico analysis of the effect of fluconazole, an antifungal drug, on DNA

In vitro and in silico analysis of the effect of fluconazole, an antifungal drug, on DNA

Increase of reactive oxygen species contributes to growth inhibition by fluconazole in Cryptococcus neoformans

<p>In vitro mitochondrial-targeted antioxidant peptide induces apoptosis in cancer cells</p>

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