title: Doxorubicin induces drug efflux pumps in Candida albicans.
abstract: Candida albicans is one of the most important opportunistic fungal pathogens. It can cause serious fungal diseases in immunocompromised patients, including those with cancer. Treatment failures due to the emergence of drug-resistant C. albicans strains have become a serious clinical problem. Resistance incidents were often mediated by fungal efflux pumps which are closely related to the human ABC transporter P-glycoprotein (P-gp). P-gp is often overexpressed in cancer cells and confers resistance to many cytotoxic drugs. We examined whether cytotoxic drugs commonly used for cancer treatment (doxorubicin and cyclophosphamide) could alter the expression of genes responsible for the development of fluconazole resistance in Candida cells in the way they can influence homologous genes in cancer cell lines. ABC transporters (CDR1 and CDR2) and other resistance genes (MDR1 and ERG11) were tested by real-time PCR for their expression in C. albicans cells at the mRNA level after induction by antineoplastic drugs. The results were confirmed by a lacZ gene reporter system and verified at the protein level using GFP and immunoblotting. We showed that doxorubicin is a potent inducer of CDR1/CDR2 expression in C. albicans at both the mRNA and protein level and thus causes an increase in fluconazole MIC values. However, cyclophosphamide, which is not a substrate of human P-gp, did not induce ABC transporter expression in C. albicans. Neither doxorubicin nor cyclophosphamide could influence the expression of the other resistance genes (MDR1 and ERG11). The induction of CDR1/CDR2 by doxorubicin in C. albicans and the resulting alteration of antifungal susceptibility might be of clinical relevance for the antifungal treatment of Candida infections occurring after anticancer chemotherapy with doxorubicin.
authors.affiliation: Charité-Universitätsmedizin Berlin, Charité Campus Mitte, Medical Department, Division of Oncology/Hematology, Berlin, Germany. grzegorz.kofla@charite.de
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Kofla
authors.forename: Vincent
authors.initials: V
authors.lastname: Turner
authors.forename: Bettina
authors.initials: B
authors.lastname: Schulz
authors.forename: Ulrike
authors.initials: U
authors.lastname: Storch
authors.forename: Daniela
authors.initials: D
authors.lastname: Froelich
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Rognon
authors.forename: Alix T
authors.initials: AT
authors.lastname: Coste
authors.forename: Dominique
authors.initials: D
authors.lastname: Sanglard
authors.forename: Markus
authors.initials: M
authors.lastname: Ruhnke
mesh_terms: D000935:Antifungal Agents / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000378:metabolism*; D001693:Biological Transport, Active; D002176:Candida albicans / Q000187:drug effects* / Q000302:isolation & purification / Q000378:metabolism; D002177:Candidiasis / Q000382:microbiology; D003520:Cyclophosphamide / Q000378:metabolism; D004317:Doxorubicin / Q000378:metabolism*; D025141:Drug Resistance, Fungal; D005656:Fungal Proteins / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism*; D016133:Polymerase Chain Reaction / Q000379:methods; D015533:Transcriptional Activation
chemical_list: D000935:Antifungal Agents; D000970:Antineoplastic Agents; D005656:Fungal Proteins; D026901:Membrane Transport Proteins; D004317:Doxorubicin; D003520:Cyclophosphamide