Antifungal activity of fluconazole in combination with lovastatin and their effects on gene expression in the ergosterol and prenylation pathways in<i>Candida albicans</i>

Song, Jia L.; Lyons, C. N.; Holleman, Scott; Oliver, Brian G.; White, Theodore C.

doi:10.1080/1369378031000137233

Cited by 58 publications

(42 citation statements)

References 26 publications

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“…Some experimental evidence supports the idea that Upc2p in C. albicans is similarly activated. First, ERG11 is upregulated following azole or lovastatin treatment (46) or during hypoxia (41). Second, C. albicans upc2⌬/upc2⌬ mutants display altered growth on a medium containing azole drugs or lacking oxygen (28).…”

Section: Increased In Vivo Upc2p Binding Correlates With Increased Exmentioning

confidence: 99%

Genomewide Location Analysis of Candida albicans Upc2p, a Regulator of Sterol Metabolism and Azole Drug Resistance

et al. 2008

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Upc2p, a transcription factor of the zinc cluster family, is an important regulator of sterol biosynthesis and azole drug resistance in Candida albicans. To better understand Upc2p function in C. albicans, we used genomewide location profiling to identify the transcriptional targets of Upc2p in vivo. A triple hemagglutinin epitope, introduced at the C terminus of Upc2p, conferred a gain-of-function effect on the fusion protein.Location profiling identified 202 bound promoters (P < 0.05). Overrepresented functional groups of genes whose promoters were bound by Upc2p included 12 genes involved in ergosterol biosynthesis (NCP1, ERG11, ERG2, and others), 18 genes encoding ribosomal subunits (RPS30, RPL32, RPL12, and others), 3 genes encoding drug transporters (CDR1, MDR1, and YOR1), 4 genes encoding transcription factors (INO2, ACE2, SUT1, and UPC2), and 6 genes involved in sulfur amino acid metabolism (MET6, SAM2, SAH1, and others). Bioinformatic analyses suggested that Upc2p binds to the DNA motif 5-VNCGBDTR that includes the previously characterized Upc2p binding site 5-TCGTATA. Northern blot analysis showed that increased binding correlates with increased expression for the analyzed Upc2p targets (ERG11, MDR1, CDR1, YOR1, SUT1, SMF12, and CBP1). The analysis of ERG11, MDR1, and CDR1 transcripts in wild-type and upc2⌬/upc2⌬ strains grown under Upc2p-activating conditions (lovastatin treatment and hypoxia) showed that Upc2p regulates its targets in a complex manner, acting as an activator or as a repressor depending upon the target and the activating condition. Taken together, our results indicate that Upc2p is a key regulator of ergosterol metabolism. They also suggest that Upc2p may contribute to azole resistance by regulating the expression of drug efflux pump-encoding genes in addition to ergosterol biosynthesis genes.Candida albicans is an important human fungal pathogen, in terms of both its clinical significance and its use as an experimental model for scientific investigation. This opportunistic pathogen is a natural component of the human flora, colonizing skin and the gastrointestinal and genitourinary tracts (4). Although many infections involve the colonization of surface mucosal membranes (oral thrush and vaginal candidiasis, for example), immunosuppressed patients can be subject to potentially lethal systemic infections (45).Many antifungal drugs used to treat C. albicans infections function by targeting ergosterol, the analogue of cholesterol in mammalian cells and the major sterol of fungal cell membranes. Polyenes, such as amphotericin B, bind directly to ergosterol and perturb general membrane functions, resulting in low selectivity and high toxicity (2, 35). Azoles, including fluconazole and voriconazole, are more widely used and target the enzyme lanosterol demethylase (Erg11p) in the ergosterol biosynthesis pathway, with the consequence that ergosterol is depleted and replaced by unusual sterols, altering the fluidity of the membrane and the activities of membrane-bound proteins (e.g., enzymes...

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Section: Increased In Vivo Upc2p Binding Correlates With Increased Exmentioning

confidence: 99%

Genomewide Location Analysis of Candida albicans Upc2p, a Regulator of Sterol Metabolism and Azole Drug Resistance

et al. 2008

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“…This structural difference may also influence the uptake of these compounds into fungal cells. However, the synergistic effects of aclarubicin and daunorubicin with fluconazole were similar, i.e., the FICIs of aclarubicin and daunorubicin were 0.0083-0.0162 and [4][5][6][7], HMG-CoA reductase inhibitors (statins) [8,9], and non-steroidal antiinflammatory drugs [10,11]. In addition to their synergistic effect with fluconazole, anthracyclines have a unique function.…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, research on compounds that have synergistic effects with azole agents has flourished. Calcineurin inhibitors [4][5][6][7], HMGCoA reductase inhibitors (statins) [8,9], and non-steroidal antiinflammatory drugs (NSAIDs) are representative examples [10,11]. Low-molecular-weight antitumor agents are divided into six classes based on their mechanism of action: antimetabolites, alkylating agents, topoisomerase inhibitors, microtubule inhibitors, microtubule depolymerizing agents, and molecular target agents.…”

Section: Introductionmentioning

confidence: 99%

In vitro Synergistic Effects of Anthracycline Antitumor Agents and Fluconazole Against Azole-Resistant Candida albicans Clinical Isolates

S¹

2013

J Dev Drugs

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“…Lovastatin reduced the intracellular growth of Salmonella enterica serovar Typhimurium in cultured macrophages, as did atorvastatin (AVA) in a mouse model (5). Lovastatin also reduced the level of in vitro infection due to Coxiella burnetii (4) and additionally reduced the growth of Candida albicans by inhibiting the sterol pathway (27).…”

mentioning

confidence: 99%

Atorvastatin Is a Promising Partner for Antimalarial Drugs in Treatment of Plasmodium falciparum Malaria

Parquet

Briolant

Torrentino-Madamet

et al. 2009

Antimicrob Agents Chemother

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Atorvastatin (AVA) is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. AVA exposure resulted in the reduced in vitro growth of 22 Plasmodium falciparum strains, with the 50% inhibitory concentrations (IC 50 s) ranging from 2.5 M to 10.8 M. A significant positive correlation was found between the strains' responses to AVA and mefloquine (r ‫؍‬ 0.553; P ‫؍‬ 0.008). We found no correlation between the responses to AVA and to chloroquine, quinine, monodesethylamodiaquine, lumefantrine, dihydroartemisinin, atovaquone, or doxycycline. These data could suggest that the mechanism of AVA uptake and/or the mode of action of AVA is different from those for other antimalarial drugs. The IC 50 s for AVA were unrelated to the occurrence of mutations in the transport protein genes involved in quinoline antimalarial drug resistance, such as the P. falciparum crt, mdr1, mrp, and nhe-1 genes. Therefore, AVA can be ruled out as a substrate for the transport proteins (CRT, Pgh1, and MRP) and is not subject to the pH modification induced by the P. falciparum NHE-1 protein. The absence of in vitro cross-resistance between AVA and chloroquine, quinine, mefloquine, monodesethylamodiaquine, lumefantrine, dihydroartemisinin, atovaquone, and doxycycline argues that these antimalarial drugs could potentially be paired with AVA as a treatment for malaria. In conclusion, the present observations suggest that AVA is a good candidate for further studies on the use of statins in association with drugs known to have activities against the malaria parasite.

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Antifungal activity of fluconazole in combination with lovastatin and their effects on gene expression in the ergosterol and prenylation pathways inCandida albicans

Cited by 58 publications

References 26 publications

Genomewide Location Analysis of Candida albicans Upc2p, a Regulator of Sterol Metabolism and Azole Drug Resistance

Genomewide Location Analysis of Candida albicans Upc2p, a Regulator of Sterol Metabolism and Azole Drug Resistance

In vitro Synergistic Effects of Anthracycline Antitumor Agents and Fluconazole Against Azole-Resistant Candida albicans Clinical Isolates

Atorvastatin Is a Promising Partner for Antimalarial Drugs in Treatment of Plasmodium falciparum Malaria

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