title: Synergistic effect of the flavonoid catechin, quercetin, or epigallocatechin gallate with fluconazole induces apoptosis in Candida tropicalis resistant to fluconazole.
abstract: Flavonoids are a class of phenolic compounds commonly found in fruits, vegetables, grains, flowers, tea, and wine. They differ in their chemical structures and characteristics. Such compounds show various biological functions and have antioxidant, antimicrobial, anti-inflammatory, and antiapoptotic properties. The aim of this study was to evaluate the in vitro interactions of flavonoids with fluconazole against Candida tropicalis strains resistant to fluconazole, investigating the mechanism of synergism. Three combinations formed by the flavonoids (+)-catechin hydrated, hydrated quercetin, and (-)-epigallocatechin gallate at a fixed concentration with fluconazole were tested. Flavonoids alone had no antifungal activity within the concentration range tested, but when they were used as a cotreatment with fluconazole, there was significant synergistic activity. From this result, we set out to evaluate the possible mechanisms of cell death involved in this synergism. Isolated flavonoids did not induce morphological changes or changes in membrane integrity in the strains tested, but when they were used as a cotreatment with fluconazole, these changes were quite significant. When evaluating mitochondrial damage and the production of reactive oxygen species (ROS) only in the cotreatment, changes were observed. Flavonoids combined with fluconazole were shown to cause a significant increase in the rate of damage and the frequency of DNA damage in the tested strains. The cotreatment also induced an increase in the externalization of phosphatidylserine, an important marker of early apoptosis. It is concluded that flavonoids, when combined with fluconazole, show activity against strains of C. tropicalis resistant to fluconazole, promoting apoptosis by exposure of phosphatidylserine in the plasma membrane and morphological changes, mitochondrial depolarization, intracellular accumulation of ROS, condensation, and DNA fragmentation.
authors.affiliation: Department of Clinical and Toxicological Analysis, School of Pharmacy, Laboratory of Bioprospection and Experiments in Yeast (LABEL), Federal University of Ceara, Fortaleza, CE, Brazil.
authors.forename: Cecília Rocha
authors.initials: CR
authors.lastname: da Silva
authors.forename: João Batista
authors.initials: JB
authors.lastname: de Andrade Neto
authors.forename: Rosana
authors.initials: R
authors.lastname: de Sousa Campos
authors.forename: Narjara Silvestre
authors.initials: NS
authors.lastname: Figueiredo
authors.forename: Letícia Serpa
authors.initials: LS
authors.lastname: Sampaio
authors.forename: Hemerson Iury Ferreira
authors.initials: HI
authors.lastname: Magalhães
authors.forename: Bruno Coêlho
authors.initials: BC
authors.lastname: Cavalcanti
authors.forename: Danielle Macêdo
authors.initials: DM
authors.lastname: Gaspar
authors.forename: Geanne Matos
authors.initials: GM
authors.lastname: de Andrade
authors.forename: Iri Sandro Pampolha
authors.initials: IS
authors.lastname: Lima
authors.forename: Glauce Socorro
authors.initials: GS
authors.lastname: de Barros Viana
authors.forename: Manoel Odorico
authors.initials: MO
authors.lastname: de Moraes
authors.forename: Marina Duarte Pinto
authors.initials: MD
authors.lastname: Lobo
authors.forename: Thalles Barbosa
authors.initials: TB
authors.lastname: Grangeiro
authors.forename: Hélio Vitoriano
authors.initials: HV
authors.lastname: Nobre Júnior
mesh_terms: D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D041022:Candida tropicalis / Q000187:drug effects*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004347:Drug Interactions; D025141:Drug Resistance, Fungal / Q000187:drug effects; D004357:Drug Synergism; D015725:Fluconazole / Q000008:administration & dosage / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D011794:Quercetin / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D017382:Reactive Oxygen Species; D002392:Catechin; D015725:Fluconazole; D011794:Quercetin; C045651:epigallocatechin gallate