Bioactive fungal metabolites

Fungi represent one of the seven kingdoms of living organisms [1] and their secondary metabolites display a broad range of biological activities. We have recently reviewed those fungal metabolites that display anticancer activity, both from terrestrial [2, 3] and marine [4] origins. We have also highlighted in these three reviews [2-4], the currently known biological events that enable various types of cancers, including metastatic ones to display high levels of chemoresistance. Some fungal metabolites are able to overcome certain of these biological barriers leading to cancer chemoresistance. For example, fusicoccin A, isolated from Fusicoccum amygdali, down-regulates focal adhesion kinase (FAK) activity and induces cytostatic activity in glioblastoma (GBM) cells [5]. Ophiobolin A, isolated from Bipolaris species, induces paraptosis in GBM cells through the disruption of internal potassium ion homeostasis [6]. GBM are highly chemoresistant [7] as melanomas against which sphaeropsidin A, isolated from Diplodia cupressi, also displays marked anticancer activity through the disruption of melanoma cell ion homeostasis [8]. We recently highlighted in a special issue of Current Medicinal Chemistry, the potential of targeting ion channels / transporters to combat various types of cancers associated with dismal prognoses [9]. Fungal metabolite-related anticancer activity is further analyzed by two contributions in the current special issue. Wolf-Rainer Abraham (Helmholtz Centre for Infection Research, Chemical Microbiology, Braunschweig, Germany) has contributed a review entitled “Fumitremorgins and Relatives – from Tremorgenic Compounds to Valuable Anti-Cancer Drugs”. Fumitremorgins are mycotoxins that can also inhibit cancer cell proliferation and impair their drug resistance. Cristina Prandi (Department of Chemistry, Universita’ degli Studi di Torino, Torino, Italy) and her collaborators have contributed a review entitled “Fungal anticancer metabolites: synthesis towards drug discovery”. Prandi and her colleagues highlight the role of total synthesis in sustaining the pharmacological development of fungal metabolites and as an alternative to isolation in the field of cancer research. The current special issue then presents five other contributions that do not relate to anticancer activity of fungal metabolites, while emphasizing a broad spectrum of other biological activities. Peter Proksch (Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany) and his colleagues have contributed a review entitled “Natural Products from Deep-SeaDerived Fungi ̶ a New Source of Novel Bioactive Compounds?”. As reported by Proksch and colleagues, up to now, over 200 new metabolites have been identified from deep-sea fungi, and it has been assumed in the literature that the unique environment of the deep sea will give rise to equally unprecedented natural products. Proksch and colleagues critically evaluate whether the data published so far really supports the notion that these fungi are a promising source of new bioactive chemical entities. Alessio Cimmino (Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Napoli, Italy) and his colleagues have contributed a review entitled “Bioactive Metabolites from Pathogenic and Endophytic Fungi of Forest Trees”. As emphasized by Cimmino and his colleagues, fungi play an important role in terrestrial ecosystems by interacting positively or negatively with plants. Furthermore, temperate forests represent an enormous reservoir of fungal diversity. The review provided by Cimmino and colleagues focuses on the secondary metabolites produced by pathogenic and endophytic fungi of forest trees with a focus on their biological activities. Andrea Chini (Departamento de Genética Molecular de Plantas, Centro Nacional de Biotecnología- Consejo Superior de Investigaciones Científicas, Madrid, Spain) and his colleagues have contributed a review entitled “Fungal production and manipulation of plant hormones”. Chini and colleagues state that among the plant molecules that regulate plant-fungus interactions, phytohormones play a critical role because they modulate various aspects of plant development, defenses and stress responses. Chini and colleagues emphasize the fact that, intriguingly, fungi can also produce phytohormones, although the actual role of fungal-produced phytohormones in plant-fungus interactions is poorly understood. Chini and colleagues thus provide an overview of the recent discoveries in fungal production of phytohormone, their putative role as endogenous fungal signals and how fungi manipulate plant hormone balance to their benefit. Maurizio Vurro (Institute of Science of Food Production, National Research Council, Bari, Italy) and his colleagues have contributed a review entitled “Fungal Phytotoxins in Sustainable Weed Management”. Vurro and colleagues reevaluate the fact that fungal phytotoxins are natural secondary metabolites produced by plant pathogenic fungi during host–pathogen interactions. The review provided by Vurro and colleagues aims to summarize studies on the possibility of using such metabolites as tools in biological and integrated weed management, for example, as novel and environmentally friendly herbicides; as biomarkers for the selection of more efficacious biocontrol agents; as templates for novel compounds; and as sources of novel mechanisms of action. Vurro and colleagues also discuss the limiting factors for utilizing these metabolites in practice. Stefano Superchi (Dipartimento di Scienze, Università della Basilicata, Potenza, Italy) and his colleagues have contributed a review entitled “Absolute Configuration Determination by Quantum Mechanical Calculation of Chiroptical Spectra: Basics and Applications to Fungal Metabolites”. Superchi and colleagues thus review the application of quantum mechanical simulations of chiroptical properties, i.e. electronic circular dichroism, optical rotation, and vibrational circular dichroism, for the assignment of the absolute configuration of naturally occurring chiral metabolites of fungal origin. REFERENCES [1] Ruggiero, M.A.; Gordon, D.P.; Orrell, T.M.; Bailly, N.; Bourgoin, T.; Brusca, R.C.; Cavalier-Smith, T.; Guiry, M.D.; Kirk, P.M. A higher level classification of all living organisms. PLoS One, 2015, 10, e0119248. [2] Evidente, A.; Kornienko, A.; Cimmino, A.; Andolfi, A.; Lefranc, F.; Mathieu, V.; Kiss, R. Fungal metabolites with anticancer activity. Nat. Prod. Rep., 2014, 31, 617-627. [3] Kornienko, A.; Evidente, A.; Vurro, M.; Mathieu, V.; Cimmino, A.; Evidente, M.; van Otterlo, W.A.; Dasari, R.; Lefranc, F.; Kiss, R. Toward a cancer drug of fungal origin. Med. Res. Rev., 2015, 35, 937-67. [4] Gomes, N.G.; Lefranc, F.; Kijjoa, A.; Kiss, R. Can some marine-derived fungal metabolites become actual anticancer agents? Mar. Drugs, 2015, 13, 3950-3991. [5] Bury, M.; Andolfi, A.; Rogister, B.; Cimmino, A.; Mégalizzi, V.; Mathieu, V.; Feron, O.; Evidente, A.; Kiss, R. Fusiccocin A, a phytotoxic carbotricyclic diterpene glucoside of fungal origin, reduces proliferation and invasion of glioblastoma cells by targeting multiple tyrosine kinases. Trans. Oncol., 2013, 6, 112-123. [6] Bury, M.; Girault, A.; Mégalizzi, V.; Spiegl-Kreinecker, S.; Mathieu, V.; Berger, W.; Evidente, A.; Kornienko, A.; Gailly, P.; Vandier, C.; Kiss, R. Ophiobolin A induces paraptosis-like cell death in human glioblastoma cells by decreasing BKCa channel activity. Cell Death Dis., 2013, 4, e561. [7] Lefranc, F.; Brotchi, J.; Kiss, R. Possible future issues in the treatment of glioblastomas: special emphasis on cell migration and the resistance of migrating glioblastoma cells to apoptosis. J. Clin. Oncol., 2005, 23, 2411-2422. [8] Mathieu, V.; Chantôme, A.; Lefranc, F.; Cimmino, A.; Miklos, W.; Paulitschke, V.; Mohr, T.; Maddau, L.; Kornienko, A.; Berger, W.; Vandier, C.; Evidente, A.; Delpire, E.; Kiss, R. Sphaeropsidin A shows promising activity against drug-resistant cancer cells by targeting regulatory volume increase. Cell Mol. Life Sci., 2015, 72, 3731-3746. [9] Kiss, R. Ion channels and cancers. Curr. Med. Chem., 2012, 19, 625-626.