Biological activities of fusarochromanone: a potent anti-cancer agent

Abstract

BackgroundFusarochromanone (FC101) is a small molecule fungal metabolite with a host of interesting biological functions, including very potent anti-angiogenic and direct anti-cancer activity.ResultsHerein, we report that FC101 exhibits very potent in-vitro growth inhibitory effects (IC50 ranging from 10nM-2.5 μM) against HaCat (pre-malignant skin), P9-WT (malignant skin), MCF-7 (low malignant breast), MDA-231 (malignant breast), SV-HUC (premalignant bladder), UM-UC14 (malignant bladder), and PC3 (malignant prostate) in a time-course and dose-dependent manner, with the UM-UC14 cells being the most sensitive. FC101 induces apoptosis and an increase in proportion of cells in the sub-G1 phase in both HaCat and P9-WT cell lines as evidenced by cell cycle profile analysis. In a mouse xenograft SCC tumor model, FC101 was well tolerated, non-toxic, and achieved a 30% reduction in tumor size at a dose of 8 mg/kg/day. FC101 is also a potent anti-angiogenenic agent. At nanomolar doses, FC101 inhibits the vascular endothelial growth factor-A (VEGF-A)-mediated proliferation of endothelial cells.ConclusionsOur data presented here indicates that FC101 is an excellent lead candidate for a small molecule anti-cancer agent that simultaneously affects angiogenesis signaling, cancer signal transduction, and apoptosis. Further understanding of the underlying FC101’s molecular mechanism may lead to the design of novel targeted and selective therapeutics, both of which are pursued targets in cancer drug discovery.

Toxic, but beneficial compounds from endophytic fungi of Carica papaya

“…Compounds with anticancer properties also isolated from F. equiseti include Diacetoxyscirpenol (54,55) and Fusarochromanone and its derivatives (56,57). Other compounds from F. equiseti are 4-acetylnivalenol, nivalenol, scirpentriol zearalenone, beauvericin, fusarochromanone, equisetine and butenolide (58,59).…”

Use of in-silico assays to characterize the ADMET profile and identify potential therapeutic targets of fusarochromanone, a novel anti-cancer agent

“…Furthermore, Fig. 2 illustrates that FC101a does not affect anti-apoptotic proteins (Bcl-2, Bcl-XL, Mcl-1) or pro-apoptotic proteins (BAD, BAK, BAX); further attesting that FC101a induces apoptotic cascades by means of an extrinsic mechanism involving caspase-8 (Mahdavian et al 2014a ). Therefore proteins upstream of caspase-3, caspase-8, and PARP were selected as potential targets, but only if unambiguous crystal structures were available through RCSB- in total 49 proteins were selected.…”

“…Since 1940, approximately 175 small molecules have been approved as anti-cancer agents; of these, 48.6 % were a natural product or derivative (Newman and Cragg 2012 ). Fusarochromanone (FC101a) is a small molecule fungal metabolite exhibiting potent in-vitro growth inhibitory effects in 35 of 58 human cancer lines through a novel mode of action (Mahdavian et al 2014a ). FC101a demonstrates a multi-focal approach to inhibiting cancer growth that includes induction of apoptosis, suppression of angiogenesis and tumorigenesis, and direct inhibition of endothelial cell growth, evident by MTT cell viability assays, FACS analysis, and western blotting (Mahdavian et al 2014a ).…”

“…Fusarochromanone (FC101a) is a small molecule fungal metabolite exhibiting potent in-vitro growth inhibitory effects in 35 of 58 human cancer lines through a novel mode of action (Mahdavian et al 2014a ). FC101a demonstrates a multi-focal approach to inhibiting cancer growth that includes induction of apoptosis, suppression of angiogenesis and tumorigenesis, and direct inhibition of endothelial cell growth, evident by MTT cell viability assays, FACS analysis, and western blotting (Mahdavian et al 2014a ). Due to these characteristics, we believe FC101a is a promising lead candidate for an anti-cancer agent effective against a broad range of cancers.…”

“…Although FC101a anti-cancer activity has been well documented, its biological target(s) and mechanism of action have remained enigmatic; according to a NCI COMPARE study, its mode of action is novel when compared to a database including 50,000 compounds (Mahdavian et al 2014a ). Furthermore, diminished in-vivo potency remains an obstacle and requires addressing- the large disparity between levels of activity in-vivo and in-vitro suggests the molecule requires structural modifications to maximize its activity.…”