This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Turbyville, T. J. Articles by Gunatilaka, A.A. L. Search for Related Content PubMed PubMed Citation Articles by Turbyville, T. J. Articles by Gunatilaka, A.A. L.

¹ Southwest Center for Natural Products Research and Commercialization, Office of Arid Lands Studies, College of Agriculture and Life Sciences and ² Section of Pediatric Hematology/Oncology, Steele Memorial Children's Research Center, The University of Arizona, Tucson, Arizona

Requests for reprints: A.A. Leslie Gunatilaka, Southwest Center for Natural Products Research, The University of Arizona, 250 East Valencia Road, Tucson, AZ 85706-6800. Phone: 520-741-1691; Fax: 520-741-1468. E-mail: leslieg{at}ag.arizona.edu

Tumors are dependent on cellular stress responses, in particular the heat shock response, for survival in their hypoxic, acidotic, and nutrient-deprived microenvironments. Using cell-based reporter assays, we have identified terrecyclic acid A (TCA) from Aspergillus terreus, a fungus inhabiting the rhizosphere of Opuntia versicolor of the Sonoran desert, as a small-molecule inducer of the heat shock response that shows anticancer activity. Further characterization suggested that TCA also affects oxidative and inflammatory cellular stress response pathways. The presence of an -methylene ketone moiety suggested that TCA may form adducts with sulfhydryl groups of proteins. Reaction with labile intracellular cysteines was supported by our finding that the glutathione precursor N-acetyl-cysteine protected tumor cells from the cytotoxic effects of TCA whereas the glutathione-depleting agent buthionine sulfoximine enhanced its activity. Related sesquiterpenes have been shown to increase levels of reactive oxygen species (ROS) and to inhibit nuclear factor B (NF-B) transcriptional activity. To assess whether TCA could have similar activities, we used a ROS-sensitive dye and flow cytometry to show that TCA does indeed increase ROS levels in 3LL cells. When tested in cells carrying NF-B reporter constructs, TCA also exhibited concentration-dependent inhibition of cytokine-induced NF-B transcriptional activity. These findings suggest that TCA modulates multiple stress pathways—the oxidative, heat shock, and inflammatory responses—in tumor cells that promote their survival. Small-molecule natural products such as TCA may serve as useful probes for understanding the relationships between these pathways, potentially providing leads for the design of novel and effective anticancer drugs.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

³ Turbyville TJ, Wijeratne EMK, Liu MX, et al. Search for Hsp90 inhibitors with potential anticancer activity: isolation and structure-activity relationship studies of radicicol and monocillin 1 from two plant-associated fungi of the Sonoran desert. J Nat Prod, submitted for publication.

Received 2/17/05; revised 7/28/05; accepted 8/11/05.