Abstract
Microorganisms isolated from an acid mine waste lake have proven an unexpected source of novel, bioactive metabolites. Berkeley Pit Lake is part of the largest Superfund site in North America. Despite its low pH, high Eh, and high metal concentration, it harbors extremophilic microbes that have been grown in the laboratory in liquid culture using an array of physicochemical conditions. Bioassay-guided fractionation has directed the purification of small molecule inhibitors of enzymes associated with inflammation (caspase-1) and epithelial-mesenchymal transition (matrix-metalloproteinase-3, MMP-3). Caspase-1 plays an important role in chronic inflammation. It is activated upon binding to the inflammasome, a multiprotein complex that plays a key role in innate immunity. Activated caspase-1 in turn activates pro-inflammatory cytokines. Up-regulation of caspase-1 and concomitant chronic inflammation have been associated with leukemia, melanoma, glioblastoma, pancreatic cancers and breast cancer. MMP-3 promotes tumor cell invasion through the loss of cellular adhesion and promotion of epithelial-mesenchymal transition, which is associated with the metastatic spread of cancer. Inflammation and metastasis are interconnected and provide important targets for chemotherapy. Novel compounds have been tested by the National Cancer Institute-Developmental Therapeutics Program, Memorial Sloan Kettering Cancer Center and Eisai, Inc. for anti-proliferative activity against specific and established human cancer cell lines. In these studies, attention has been paid to the isolation and characterization of enzyme inhibitors as well as inactive analogues to facilitate assessment of structure/activity relationships. Compounds isolated using this methodology have demonstrated activity against specific cancer cell lines, and some of these compounds will be described.
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Stierle, A.A., Stierle, D.B. (2017). Secondary Metabolites of Mine Waste Acidophilic Fungi. In: Paterson, R., Lima, N. (eds) Bioprospecting. Topics in Biodiversity and Conservation, vol 16. Springer, Cham. https://doi.org/10.1007/978-3-319-47935-4_10
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