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Introduction
Ophiobolins are secondary metabolites belonging to the family of sesterterpenoid compounds and are produced by phytopathogenic fungi, mainly of the genus Bipolaris. Their discovery filled the gap between diterpenes (C20), which have four isoprene units and triterpenes (C30), which have six isoprene units (1). Ophiobolin A was the first member of the group to be isolated and characterized in the mid-1960s (2,3). Currently, 25 biogenic ophiobolins have been identified and marine-derived fungal ophiobolins were recently identified and demonstrated to inhibit the biofilm formation of Mycobacterium species (4).
Ophiobolin-producing terrestrial fungi attack several crops, such as rice, maize and sorghum, by causing brown spot lesions on the leaves. These fungi mainly attack monocotyledons, but they can also attack various herbaceous dicotyledon species, although grass weeds proved to be more sensitive to the phytotoxins (5). The interest in Bipolaris spp. and their bioactive metabolites derives from their previous implication in two devastating plant disease epidemics: the Bengal rice famine in India in 1943 and the Southern corn leaf blight epidemic in the USA in 1972 (1).
Ophiobolins can lead to cell death in plants through multiple mechanisms of action, including inhibition of root and coleoptile growth in wheat seedlings, inhibition of seed germination, changes in cell membrane permeability, stimulation of β-cyanin leakage, releases of electrolytes and glucose from the roots and decreases in photosynthetic CO2-fixation, which cause respiratory changes and enhance stomatal opening (reviewed in ref. 1). Ophiobolin A is able to inhibit protein and nucleic acid synthesis or act as an inhibitor of β-1,3-glucan synthetase in plant cells (1).
While a body of information on the deleterious effects of ophiobolin A in plants is already available, only a few of these reports mention the anticancer effects of ophiobolin A and these reports are limited to in vitro studies. Cytotoxic effects were reported for ophiobolin A (6,7) and ophiobolin O (8) but not for ophiobolin I (6) in various cancer cell lines.
The present study further aims to characterize ophiobolin A-mediated effects on cell proliferation versus cell death in normal plant (tobacco) versus normal mammalian cells and then in mammalian cancer cells.
Materials and methods
Ophiobolin A production and stability
Fungus
A strain of Drechslera gigantea (Heald & Wolf) was used to...