Anticancer drug discovery from filamentous fungi

Members of our team have a long history in the discovery of anticancer leads from plants, most notably taxol and camptothecin. Recent efforts have focused on under-investigated source materials, especially microorganisms that can be grown in culture. Filamentous fungi are found throughout the environment, where one of their roles is to cycle carbon via decomposition of organic matter. These organisms have been collected from around the world, resulting in a unique library of ˜55,000 isolates maintained at Mycosynthetix. This library has revealed leads for both human diseases and agrochemical applications. However, until now, it had not been examined systematically for anticancer leads.

Cultures were selected based on morphology and collection site. A two-stage culture process was utilized, whereby pure starter cultures grown in a malt extract medium were inoculated onto a solid, rice-based medium. Following incubation of 10–20 days, cultures were extracted and organic- and aqueous-soluble fractions were generated; both were examined for cytotoxicity against a human cancer cell panel. Promising leads were studied in a tumor selectivity assay, which employs MCF-7 and MCF10a cells, the latter being a proliferative, but non-tumorigenic cell line. Priority was given to samples with potent, cancer cell specific cytotoxicity.

Via this approach, our team has identified several promising leads in various stages of bioactivity-directed fractionation. For example, a fungus collected in Boca Raton, FL yielded a pair of known compounds with potent cytotoxicity. Moreover, a new cyclic peptide has been isolated that displays the much desired cancer cell selectivity; structure elucidation studies are ongoing.

Acknowledgements: This research was supported by grant P01 CA125066–01A1 from NCI/NIH, Bethesda, MD, U.S.A.