Abstract
Cladosporium species are endophytic fungi that grow on organic matter and are considered food contaminants. The anti-microbial and anti-tumor naphthoquinones fusarubin (FUS) and anhydrofusarubin (AFU) were isolated using column chromatography from a Cladosporium species residing inside Rauwolfia leaves. The impact of FUS and AFU on cell growth was assessed in acute myeloid leukemia (OCI-AML3) and other hematologic tumor cell lines (HL-60, U937, and Jurkat). Treatment with FUS or AFU reduced the number of OCI-AML3 cells as evaluated by a hemocytometer. Flow cytometry analyses showed that this effect was accompanied by diverse impairments in cell cycle progression. Specifically, FUS (20 or 10 μg/mL significantly decreased the percentage of cells in S phase and increased the percentage of cells in G2/M phase, whereas AFU increased the percentage of cells in G0/G1 phase (50 and 25 μg/mL) and decreased the percentage of cells in S (50 μg/mL) and G2/M (50 and 25 μg/mL) phases. Both substances significantly increased apoptosis at higher concentrations. The effects of FUS were more potent than those of AFU, with FUS up-regulating p21 expression in a p53-dependent manner, as detected by Western blot analyses, likely the consequence of decreased ERK phosphorylation and increased p38 expression (both of which increase p21 stability). FUS also decreased Akt phosphorylation and resulted in increased Fas ligand production and caspase-8/3-dependent apoptosis. These results suggest that FUS and AFU inhibit proliferation and increase apoptosis in cell lines derived from hematological cancers.
Highlights
Endophytic fungi interact with host plants and alter aspects of their physiology [1], conferring increased tolerance to stress [2], improving immune system function [3], bolstering defenses against disease [4], and aiding substance absorption [5]
FUS decreased Akt phosphorylation and resulted in increased Fas ligand production and caspase-8/3-dependent apoptosis. These results suggest that FUS and AFU inhibit proliferation and increase apoptosis in cell lines derived from hematological cancers
We analyzed in detail how FUS and AFU affect proliferation and apoptosis to better understand their biological actions. We found that both substances interfered with the cell cycle and increased apoptosis in hematological cancer cell lines
Summary
Endophytic fungi interact with host plants and alter aspects of their physiology [1], conferring increased tolerance to stress [2], improving immune system function [3], bolstering defenses against disease [4], and aiding substance absorption [5]. Endophytic Cladosporium species, such as Cladosporium fulvum, allow the expression of plant genes that code for resistance to pathogens, providing long-term protection [9]. These endophytic fungi cause human diseases such as unilateral cervical lymphadenopathy [10] and acne-like subcutaneous phaeohyphomycosis [11]. They can be used to derive bioactive compounds, such as the anti-cancer drug paclitaxel [12]. Studying the interaction between fungi such as Cladosporium sp
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