A fungal source of a desired anticancer agent is of particular value, as fungal fermentation provides a virtually inexhaustible source of desired metabolites. As natural products chemists turn their attention to endophytic fungi, the number of new compounds isolated should increase over the next five years. Many of the compounds discussed in this review had IC50 values comparable to those of the standard reference drugs, making the search for anticancer compounds isolated from endophytic fungi a promising one. Novel compounds or previously isolated compounds are readily available and accessible to whatever specific anticancer screens researchers use for isolation and evaluation. As our understanding of the mechanisms associated with the onset and metastasis of cancers increases, our ability to use this knowledge to select for ever more potent and selective compounds should increase commensurately. Endophytic fungi will continue to provide a fertile arena for these quests.
endophytic fungi, anticancer compounds
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Yew species (Taxus spp.) throughout the world are hosts to hundreds, or perhaps thousands, of endophytic organisms. Most commonly, these organisms are fungi, living in a commensal or a symbiotic relationship with their host plant, so the plants exhibit little or no outward evidence that they are supporting these microorganisms. Little is known about any of the biochemical mechanisms that mediate the interactions between the yew host and its associated microbes. We feel that such information may not only contribute to our understanding of endophyte-tree biology, but also may provide novel pharmaceutical leads, because some of the compounds produced by these endophytes have demonstrated pharmacological activities. Acremonium sp. was isolated as an endophytic fungus of the European yew, Taxus baccata. Entry of Acremonium sp. into the plant may proceed via invasion of natural openings such as stomata. The relationship between Acremonium sp. and T. baccata may be a symbiotic one, because no symptoms are seen when Taxus media p.v. Hicksii is inoculated with this fungus. In culture, the fungus makes leucinostatin A, a peptide with phytotoxic, anticancer and antifungal properties. Although this peptide causes necrotic symptoms in many non-host plants and other cell types, it causes no visible symptoms in the host plant. T. baccata and several other plants have a UDP glucose; leucinostatin A glucosyl transferase that catalyzes the production of leucinostatin A β di-O-glucoside from leucinostatin A. This glucoside, also made by the fungus, has a lower bioactivity against plants, fungi and a breast cancer cell line, BT-20, than leucinostatin A. Leucinostatin A may be one of several potentially toxic peptides produced by Acremonium sp. that contribute to the defense of the host, thereby preserving the fungus' own biological niche. The host plant is relatively immune to leucinostatin A because it has an enzyme which transfers two glycosyl residues to leucinostatin A, markedly reducing the peptide's bioactivity. Our results suggest that glucosylation reactions may play a more general role in plant defenses, especially against toxin-mediated disease development
toxicity, endophyte, cancer, leucinostatin A, yew
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