Global disruption of cell cycle progression and nutrient response by the antifungal agent amiodarone

Yong Qiang Zhang, Rajini Rao

Research output: Contribution to journalArticle

Abstract

The antiarrhythmic drug amiodarone has fungicidal activity against a broad range of fungi. In Saccharomyces cerevisiae, it elicits an immediate influx of Ca2+ followed by mitochondrial fragmentation and eventual cell death. To dissect the mechanism of its toxicity, we assessed the transcriptional response of S. cerevisiae to amiodarone by DNA microarray. Consistent with the drug-induced calcium burst, more than half of the differentially transcribed genes were induced by high levels of CaCl2. Amiodarone also caused rapid nuclear accumulation of the calcineurin-regulated Crz1. The majority of genes induced by amiodarone within 10 min were involved in utilization of alternative carbon and nitrogen sources and in mobilizing energy reserves. The similarity to nutrient starvation responses seen in stationary phase cells, rapamycin treatment, and late stages of shift to diauxic conditions and nitrogen depletion suggests that amiodarone may interfere with nutrient sensing and regulatory networks. Transcription of a set of nutrient-responsive genes was affected by amiodarone but not CaCl2, indicating that activation of the starvation response was independent of Ca2+. Genes down-regulated by amiodarone were involved in all stages of cell cycle control. A moderate dose of amiodarone temporarily delayed cell cycle progression at G1, S, and G2/M phases, with the Swe1-mediated delay in G 2/Mphase being most prominent in a calcineurin-dependent manner. Overall, the transcriptional responses to amiodarone revealed by this study were found to be distinct from other classes of antifungals, including the azole drugs, pointing toward a novel target pathway in combating fungal pathogenesis.

Original languageEnglish (US)
Pages (from-to)37844-37853
Number of pages10
JournalJournal of Biological Chemistry
Volume282
Issue number52
DOIs
StatePublished - Dec 28 2007

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this