Econazole is an azole antifungal with anticancer activity that blocks Ca(2+) influx and stimulates endoplasmic reticulum (ER) Ca(2+) release through the generation of mitochondrial reactive oxygen species (ROS), resulting in sustained depletion of ER Ca(2+) stores, protein synthesis inhibition, and cell death. c-Myc, a commonly activated oncogene, also promotes apoptosis in response to growth factor withdrawal and a variety of chemotherapeutic agents. We have investigated the role of c-myc in regulating sensitivity to econazole. Here, we show that c-myc-negative cells are profoundly resistant to econazole. c-Myc-negative rat fibroblasts failed to generate mitochondrial ROS in response to econazole and consequently failed to deplete the ER of Ca(2+). HL60 cells knocked down for c-myc expression also displayed decreased ROS generation and decreased econazole sensitivity. Addition of H(2)O(2) restored sensitivity to econazole in both c-myc-negative rat fibroblasts and c-myc knocked-down HL60 cells, supporting a role for ROS in cell death induction. c-Myc-negative cells and HL60 cells knocked down for c-myc have reduced mitochondrial content compared with c-myc-positive cells. The hypoxia sensor, hypoxia-inducible factor-1alpha (HIF-1alpha), interacts antagonistically with c-myc and also regulates mitochondrial biogenesis. Knockdown of HIF-1alpha in c-myc-negative cells increased mitochondrial content restored ROS generation in response to econazole and increased sensitivity to the drug. Taken together, these results show that c-myc and HIF-1alpha regulate sensitivity to econazole by modulating the ability of the drug to generate mitochondrial ROS. [Mol Cancer Ther 2008;7(3):483-91].

Yu Y, Niapour M, Zhang Y, Berger SA.

Arthritis and Immune Disorder Research Centre, University Health Network, Toronto Medical Discovery Tower, 8th Floor, Room 8-354, 101 College Street, Toronto, Ontario, Canada M5G 1L7. berger@uhnres.utoronto.ca.