 Abstract: The soil fungus Penicillium pinophilum has been described as an ecological antagonist and a mycoparasite of the widespread plant pathogen Rhizoctonia solani. Its antifungal properties have been reported in relation to the production of 3-O-methylfunicone (OMF), an extrolite characterized by liquid cultures of an isolate of this species (LT4) that is patented by CRA (Italian patent no. 01308189, 2001). OMF is able to inhibit hyphal growth of R. solani and other plant pathogenic and dermatophytic fungi in vitro at a concentration of 0.1 mg/ml. Fungitoxicity is also evident after treatment of actively growing cultures, where the integrity of the hyphal structure appear to be compromised, cells collapse, and their membranes are degraded. In addition, antiproliferative and pro-apoptotic properties have resulted on several human tumour cell-lines (Hep-2, HeLa, MCF-7, A549, A375M). Particularly, the compound is responsible of a cytostatic effect associated to evident morphological changes and modifications in the organization of tubulin fibres. In fact, chemical structure of OMF is based on a substituted gamma-pyrone ring connected to a tri-methoxylated aryl nucleus; this moiety, which also characterizes other known antitumor compounds such as combretastatin, staganacin, the podophyllotoxins, and the chalcones, is thought to interact with tubulins by binding at their sulphydryl groups. OMF also affects expression of genes involved in the cell cycle, which is arrested in the G1 phase, with a significant increase in p21 mRNA expression, and a decrease in cyclin D1 and Cdk4 mRNA. Apoptosis induction has been confirmed by DNA-laddering, annexin assay, and cytofluorimetric analysis of the DNA content of the sub-G1 fraction; the triggered apoptotic pathway is p53 independent. In MCF-7 cells, pro-apoptotic effects also depend on a down-regulation of tumor-associated antigens, such as survivin and hTERT. Finally, anti-metastatic effects may derive by the ability of OMF to affect cell motility, in connexion with down-regulation of alpha-v-beta-5 integrin and inhibition of matrix metalloproteinases. The reported effects of OMF are indicative of a potential for the development of a new agent for cancer chemotherapy.
|
