The anticancer activity of the fungal metabolite terrecyclic acid A is associated with modulation of multiple cellular stress response pathways.
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 alpha-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 kappaB (NF-kappaB) 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-kappaB reporter constructs, TCA also exhibited concentration-dependent inhibition of cytokine-induced NF-kappaB 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.
Turbyville
Thomas J
TJ
Southwest Center for Natural Products Research and Commercialization, Office of Arid Lands Studies, College of Agriculture and Life Sciences, The University of Arizona, Tucson, AZ 85706-6800, USA.
Wijeratne
E M Kithsiri
EM
Whitesell
Luke
L
Gunatilaka
A A Leslie
AA
D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001230:Aspergillus / Q000737:chemistry; D048708:Cell Growth Processes / Q000187:drug effects; D005434:Flow Cytometry; D006367:HeLa Cells; D018869:Heat-Shock Response / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000032:analysis / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; C036622:terrecyclic acid A